rs111033313

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.919-2A>G variant causes a splice acceptor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000775 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000066 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:23O:2

Conservation

PhyloP100: 8.43

Variant links:

Genes affected

SLC26A4 (HGNC:8818): (solute carrier family 26 member 4) Mutations in this gene are associated with Pendred syndrome, the most common form of syndromic deafness, an autosomal-recessive disease. It is highly homologous to the SLC26A3 gene; they have similar genomic structures and this gene is located 3' of the SLC26A3 gene. The encoded protein has homology to sulfate transporters. [provided by RefSeq, Jul 2008]

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 22 ACMG points.

PVS1

Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 7-107683453-A-G is Pathogenic according to our data. Variant chr7-107683453-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 4840.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-107683453-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.919-2A>G		splice_acceptor_variant		ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.919-2A>G		splice_acceptor_variant			NM_000441.2	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00538

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000359

AC:

AN:

251010

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135682

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00479

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727024

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00227

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000190

AC:

AN:

152346

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00539

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000276

ExAC

AF:

0.000305

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Other:2

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:9Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	clinical testing	The Core Laboratory in Medical Center of Clinical Research, Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine	May 12, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Sep 20, 2018	The filtering allele frequency of the c.919-2A>G variant in the SLC26A4 gene is 0.4% for East Asian chromosomes in the Genome Aggregation Database (91/18860 with 95% CI) , which meets the allele frequency threshold defined by the ClinGen Hearing Loss Expert Panel for considering strong evidence against pathogenicity for autosomal recessive hearing loss variants (BS1). However, the c.919-2A>G variant in SLC26A4 is predicted to cause the skipping of a biologically-relevant out-of-frame exon 8. This is then expected to lead to a truncated or absent protein in a gene in which loss-of-function is an established disease mechanism (PVS1; PMID: 30192042). Additionally, this variant has been detected in 16 patients with hearing loss in trans with more than 4 pathogenic variants (PM3_VeryStrong; PMID: 23151025). The c.919-2A>G variant in SLC26A4 has been reported to segregate with hearing loss in at least 6 family members (PP1_Strong; 10874637). Therefore, the BS1 code will not contribute to the overall classification. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Pendred syndrome based on the ACMG/AMP criteria applied: PVS1, PP1_Strong, PM3_VeryStrong, BS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_000441.1(SLC26A4):c.919-2A>G is a canonical splice variant classified as pathogenic in the context of Pendred syndrome. c.919-2A>G has been observed in cases with relevant disease (PMID: 18641518). Functional assessments of this variant are not available in the literature. c.919-2A>G has been observed in population frequency databases (gnomAD: EAS 0.49%). In summary, NM_000441.1(SLC26A4):c.919-2A>G is a canonical splice variant in a gene where loss of function is a known mechanism of disease, is predicted to disrupt protein function, and has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 08, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 08, 2021	Variant summary: SLC26A4 c.919-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in skipping of exon 8 although low levels of normal transcript were also reported in tissues from patients homozygous for this variant (example Lee_2014). The variant allele was found at a frequency of 0.00036 in 251010 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00036 vs 0.0035), allowing no conclusion about variant significance. c.919-2A>G has been widely reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coucke_1999, Li_2012). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and an expert panel (ClinGen Hearing Loss Variant Curation Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jun 24, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with deafness with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. RNA analysis using patient cells showed an out-of-frame skipping of exon 8 which resulted in a frameshift and a premature termination codon, and subsequent nonsense-mediated decay of the resulting protein (PMID: 15574297). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 103 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar, DECIPHER). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with non-syndromic enlarged vestibular aqueduct and Pendred syndrome (ClinVar, PMID: 25372295). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change affects an acceptor splice site in intron 7 of the SLC26A4 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs111033313, gnomAD 0.5%). Disruption of this splice site has been observed in individual(s) with Pendred syndrome or non-syndromic hearing loss (PMID: 10874637, 11502831). It is commonly reported in individuals of East Asian ancestry (PMID: 11502831, 16711435, 23958391, 24007330). This variant is also known as IVS8-2A>G and 1143-2A>G. ClinVar contains an entry for this variant (Variation ID: 4840). Studies have shown that disruption of this splice site results in skipping of exon 8 and introduces a premature termination codon (PMID: 15574297). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 22, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect; variant results in skipping of exon 8 and a new stop codon at position 348 (Lu et al., 2014); This variant is associated with the following publications: (PMID: 16711435, 20842945, 19786220, 23469187, 21811566, 25525159, 26100058, 20301640, 28505178, 28786104, 27308839, 28640090, 29106878, 28901477, 31442870, 30282152, 30589569, 30693673, 29234782, 31347505, 31035178, 30473558, 30036422, 31107121, 30268946, 29681450, 30554688, 31599023, 31980526, 32203226, 30896630, 32425884, 24338212, 15574297, 11502831, 21961810, 23151025, 27176802, 27498126, 24007330, 10874637, 28925492, 28981942, 28093008, 28964290, 30086623, 31415960, 30970410, 30898719, 30762457, 29921047, 29634755, 27729126, 27240500, 30733538, 30842343, 31692010, 31564438, 32574949, 29650690, 31914302, 31541171, 31827275, 30275481, 31656273, 15905611, 34426522, 32877901, 34170635, 33614372, 32447495, 33724713, 32645618, 33597575, 33638616, 25231367, 17718863, 30311386, 15679828, 14508505, 23958391) -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:5Other:1

Pathogenic, no assertion criteria provided	case-control	Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital	Feb 26, 2019	- -
Affects, no assertion criteria provided	clinical testing;in vitro	National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center	Aug 20, 2019	in vitro experiment -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Hearing and Balance Research, National Hospital Organization Tokyo Medical Center	Jul 01, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 30, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	The variant was co-segregated with Deafness, autosomal recessive 4 in multiple affected family members with additional meioses meeting strong evidence levels (PMID: 10874637) (PP1_S). Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region (PVS1_VS).The variant has been reported multiple times as an established pathogenic/likely pathogenic variant (ClinVar ID: VCV000004840, 3billion dataset). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000365, PM2_M). The same variant was previously reported several times in trans with another pathogenic variant in this gene (PMID: 23151025, PM3_VS). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2009	- -

Hearing loss, autosomal recessive

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 01, 2011

The 919-2A>G variant in SLC26A4 has been reported in over 400 individuals with n onsyndromic hearing loss or Pendred syndrome (Coucke 1999, Yong 2001, Park 2003, Tsukamoto 2003, Park 2005, Dai 2008). This variant was found to segregate with Pendred syndrome in two large families (Coucke 1999, Iwasaki 2006). In addition, is predicted to cause abnormal splicing because the nucleotide substitution occ urs in the invariant region of the splice consensus sequence. In summary, this v ariant meets our criteria to be classified as pathogenic. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 22, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.30

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AL_spliceai

1.0

Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over