chr7-107661637-A-G

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PM2PP3_ModeratePP5_Very_Strong

The NM_000441.2(SLC26A4):​c.-3-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000392 in 1,559,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 splice_acceptor

Scores

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 1.08
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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 20 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) 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: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 7-107661637-A-G is Pathogenic according to our data. Variant chr7-107661637-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43486.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107661637-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.-3-2A>G splice_acceptor_variant ENST00000644269.2
SLC26A4-AS1NR_028137.1 linkuse as main transcriptn.162T>C non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.-3-2A>G splice_acceptor_variant NM_000441.2 P1O43511-1
SLC26A4-AS1ENST00000668981.1 linkuse as main transcriptn.222T>C non_coding_transcript_exon_variant 1/2

Frequencies

GnomAD3 genomes
AF:
0.000256
AC:
39
AN:
152200
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000241
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:
0.000412
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000118
AC:
20
AN:
168934
Hom.:
0
AF XY:
0.000108
AC XY:
10
AN XY:
92282
show subpopulations
Gnomad AFR exome
AF:
0.000219
Gnomad AMR exome
AF:
0.00
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:
0.000233
Gnomad OTH exome
AF:
0.000214
GnomAD4 exome
AF:
0.000407
AC:
573
AN:
1407344
Hom.:
0
Cov.:
30
AF XY:
0.000395
AC XY:
275
AN XY:
696384
show subpopulations
Gnomad4 AFR exome
AF:
0.0000307
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000503
Gnomad4 OTH exome
AF:
0.000409
GnomAD4 genome
AF:
0.000256
AC:
39
AN:
152200
Hom.:
0
Cov.:
32
AF XY:
0.000188
AC XY:
14
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.000241
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:
0.000412
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000124
Hom.:
0
Bravo
AF:
0.000193

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pendred syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpDec 02, 2022Variant summary: SLC26A4 c.-3-2A>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 canonical 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 168934 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.00012 vs 0.0035), allowing no conclusion about variant significance. c.-3-2A>G has been reported in the literature in individuals affected with Pendred Syndrome or hearing loss (Rodriguez-Paris_2010, Sloan-Heggen_2016, Yoon_2020), and these patients were reported as compound heterozygous with other (likely) pathogenic variants. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Likely pathogenic, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Jan 03, 2020NM_000441.1(SLC26A4):c.-3-2A>G is classified as likely pathogenic in the context of Pendred syndrome. Sources cited for classification include the following: PMID: 25394566, 21704276, 23965030 and 16570074. Classification of NM_000441.1(SLC26A4):c.-3-2A>G is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteDec 21, 2023Based 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, autosomal recessive 4, with enlarged vestibular aqueduct (MIM#600791) and Pendred syndrome (MIM#274600). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (39 heterozygotes, 0 homozygotes). (SP) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is moderately conserved. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic in both compound heterozygous and homozygous individuals (ClinVar, deafnessvariationdatabase). (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:3
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 29, 2024This sequence change falls in intron 1 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs397516411, gnomAD 0.02%). This variant has been observed in individuals with SLC26A4-related conditions (PMID: 16570074, 25394566, 26022370). This variant is also known as IVS1-2A>G or IVS1-3-2A>G. ClinVar contains an entry for this variant (Variation ID: 43486). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2022SLC26A4: PM3:Very Strong, PVS1:Strong, PM2 -
Pathogenic, criteria provided, single submitterclinical testingGeneDxDec 20, 2021Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31980526, 19204907, 25525159, 21704276, 23965030, 15689455, 14679580, 16570074, 25394566, 26022370) -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 21, 2024- -
SLC26A4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesDec 04, 2023The SLC26A4 c.-3-2A>G variant is located in the 5' untranslated region. This variant is predicted to disrupt the AG acceptor site and interfere with normal splicing. This variant has been reported in multiple patients as causative for autosomal recessive Pendred syndrome or nonsyndromic hearing loss with/without enlarged vestibular aqueduct (described as IVS1-3-2A>G, Albert. 2006. PubMed ID: 16570074; described as c.3-2A>G, Soh. 2015. PubMed ID: 25394566; Yoon. 2020. PubMed ID: 32658404; DeLuca. 2015. PubMed ID: 26022370). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineJun 04, 2018The c.-3-2A>G variant in SLC26A4 has been identified in 11 compound heterozygous individuals and 1 homozygous individual with hearing loss and clinical features of DFNB4-related hearing loss/Pendred syndrome (EVA or temporal bone abnormalit ies and one with a goiter) (Lopez-Bigas 2001, Pryor 2005, Albert 2006, Choi 2009 a, Choi 2009b, Soh 2015, DeLuca 2015, LMM data). This variant has also been iden tified in 21/88534 European chromosomes by the Genome Aggregation Database (gnom AD, http://gnomad.broadinstitute.org). Although this variant has been seen in th e general population, its frequency is low enough to be consistent with a recess ive carrier frequency. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. In summary, this variant meets criteria to be classified as pathogenic for DFNB4-related hearing loss/Pendred syndrome in an autosomal recessive manner based upon presence in affected individuals and predi cted impact on protein. ACMG/AMP Criteria applied: PVS1, PM3_VeryStrong, PS4, PM 2_Supporting -
Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsMay 09, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.57
CADD
Pathogenic
26
DANN
Benign
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.83
Position offset: 12
DS_AL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs397516411; hg19: chr7-107302082; API