7-107683538-G-A

Position:

chr7-107683538-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1001+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.000282 in 1,612,484 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 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:24O:2

Conservation

PhyloP100: 6.97

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 9.1, offset of 40, new splice context is: tcaGTaagt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-107683538-G-A is Pathogenic according to our data. Variant chr7-107683538-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 4819.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107683538-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1001+1G>A		splice_donor_variant		ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1001+1G>A		splice_donor_variant			NM_000441.2	ENSP00000494017	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000196

AC:

AN:

250282

Hom.:

AF XY:

0.000214

AC XY:

AN XY:

135244

show subpopulations

Gnomad AFR exome

AF:

0.0000617

Gnomad AMR exome

AF:

0.0000580

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000288

AC:

420

AN:

1460326

Hom.:

Cov.:

AF XY:

0.000259

AC XY:

188

AN XY:

726558

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000361

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.000223

AC:

AN:

152158

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000313

Hom.:

Bravo

AF:

0.000242

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000198

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:8Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 06, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000441.1(SLC26A4):c.1001+1G>A is classified as pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID 11317356 and 9618167. Classification of NM_000441.1(SLC26A4):c.1001+1G>A is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	Apr 12, 2021	PVS1_Strong, PS1_Strong, PM2_Supporting, PM3_Moderate, PP4_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 31, 2022	Variant summary: SLC26A4 c.1001+1G>A 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: Three predict the variant abolishes the canonical 5' splicing donor site. However, to our knowledge, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 250282 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.1001+1G>A has been reported in the literature in multiple individuals affected with Pendred Syndrome (example, Coyle_1998, Pera_2008). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not provided

Pathogenic:8

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)	Aug 17, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 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; This variant is associated with the following publications: (PMID: 24224479, 10718825, 9618167, 22975760, 23273637, 25525159, 11919333, 18285825, 11317356, 14508505, 17309986, 20597900, 15689455, 25214170, 26744121, 20301640, 9618166, 30484383, 24963352, 31827275, 31980526, 31589614) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change affects a donor splice site in intron 8 of the SLC26A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant is present in population databases (rs80338849, gnomAD 0.04%). Disruption of this splice site has been observed in individuals with Pendred syndrome (PMID: 9618167, 24224479, 26744121). ClinVar contains an entry for this variant (Variation ID: 4819). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 10, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -
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	Revvity Omics, Revvity	Sep 08, 2019	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Jun 30, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 12, 2017	The, NM_000441.1(SLC26A4):c.1001+1G>A heterozygous splice variant was identified in intron 8 of SLC26A4. This substitution is predicted to cause aberrant splicing of exon 8 in SLC26A4 and may result in a truncated protein; further testing via RNA studies are required to confirm if splicing is altered. The nucleotide at this position has moderate conservation (100 vertebrates, UCSC). In silico software predictions of the pathogenicity of this variant indicate this variant causes loss of a splice donor site (NetGene2, Fruit fly, Human Splicing Finder). This variant is present in the gnomAD population database at a frequency of 0.019% and it has been previously reported in patients with autosomal recessive Pendred syndrome (Clinvar/Deafness Variation Database). Based on current information and in association with the NM_000441.1(SLC26A4):c.707T>C missense variant , this variant has been classified as PATHOGENIC. The presence of these two variants suggests a possible compound heterozygous mode of inheritance which is consistent with autosomal recessive Pendred syndrome. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

SLC26A4-related disorder

Pathogenic:2Other:1

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 04-26-2021 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The SLC26A4 c.1001+1G>A variant is a well-known splice donor variant that leads to aberrant splicing and accounts for approximately 14% of disease-causing alleles in persons of northern European descent (Alasti et al. 2014). Across a selection of the available literature, the c.1001+1G>A has been identified in a total of 53 individuals with hearing loss or Pendred syndrome, including four homozygotes, 17 compound heterozygotes, and 32 heterozygotes where a second variant was not identified (Coyle et al. 1998; Bogazzi et al. 2000; Campbell et al. 2001; Fugazzola et al. 2002; Tsukamoto et al. 2003; Bogazzi et al. 2004; Pryor et al. 2005; Madden et al. 2007; Pera et al. 2008; Pourova et al. 2010). The c.1001+1G>A variant is absent from over 500 controls and is reported at a frequency of 0.00052 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the c.1001+1G>A variant is classified as pathogenic for SLC26A4-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 25, 2024	The SLC26A4 c.1001+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant has been documented as causative for Pendred syndrome and nonsyndromic hearing loss with enlarged vestibular aqueduct (EVA) (Coyle et al.1998. PubMed ID: 9618167; Ladsous et al. 2014. PubMed ID: 24224479; Beck et al. 2015. PubMed ID: 25214170). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in SLC26A4 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 13, 2017

The c.1001+1G>A variant in SLC26A4 has been previously described in the literatu re in individuals with Pendred syndrome/DFNB4 with well-established pathogenicit y (Coyle 1998, Campbell 2001, Bogazzi 2000, Lopez-Bigas 2001, Fugazzola 2002, Ts ukamoto 2003, Bogazzi 2004, Pryor 2005, Madden 2007, Pera 2008, Pourova 2010). T his variant is present in 47/125744 European chromosomes by the Genome Aggregati on Database; however, this frequency is low enough to be consistent with a carri er frequency for recessive hearing loss or Pendred syndrome (gnomAD, http://gnom ad.broadinstitute.org; dbSNP rs80338849). This variant occurs in the invariant r egion (+/- 1,2) of the splice consensus sequence and is predicted to cause alter ed splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive DFNB4/Pend red syndrome based on the previously reported biallelic occurrences in affected individuals, association with specific clinical features, a low frequency in the general population, and predicted impact to the protein. ACMG/AMP criteria appl ied: PVS1, PS4. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

1.0

MutationTaster

Benign

1.0

GERP RS

5.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.78

Position offset: 39

DS_DL_spliceai

0.99

Position offset: -1

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