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
Consequence
NM_000441.2 splice_acceptor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.-3-2A>G | splice_acceptor_variant | ENST00000644269.2 | |||
SLC26A4-AS1 | NR_028137.1 | n.162T>C | non_coding_transcript_exon_variant | 1/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.-3-2A>G | splice_acceptor_variant | NM_000441.2 | P1 | ||||
SLC26A4-AS1 | ENST00000668981.1 | n.222T>C | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes AF: 0.000256 AC: 39AN: 152200Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000118 AC: 20AN: 168934Hom.: 0 AF XY: 0.000108 AC XY: 10AN XY: 92282
GnomAD4 exome AF: 0.000407 AC: 573AN: 1407344Hom.: 0 Cov.: 30 AF XY: 0.000395 AC XY: 275AN XY: 696384
GnomAD4 genome AF: 0.000256 AC: 39AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14AN XY: 74356
ClinVar
Submissions by phenotype
Pendred syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 02, 2022 | Variant 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 submitter | clinical testing | Myriad Genetics, Inc. | Jan 03, 2020 | NM_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 submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Dec 21, 2023 | 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, 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 submitter | clinical testing | Invitae | Jan 29, 2024 | This 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 submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | SLC26A4: PM3:Very Strong, PVS1:Strong, PM2 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2021 | Canonical 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 submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 21, 2024 | - - |
SLC26A4-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 04, 2023 | The 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 submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 04, 2018 | The 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 submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 09, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at