7-107710126-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.2162C>T(p.Thr721Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000174 in 1,607,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T721K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000441.2 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.2162C>T | p.Thr721Met | missense_variant | 19/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.2162C>T | p.Thr721Met | missense_variant | 19/21 | NM_000441.2 | P1 | ||
SLC26A4 | ENST00000644846.1 | c.*64C>T | 3_prime_UTR_variant, NMD_transcript_variant | 8/10 | |||||
SLC26A4 | ENST00000492030.2 | n.377-29C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251252Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135780
GnomAD4 exome AF: 0.0000165 AC: 24AN: 1454996Hom.: 0 Cov.: 28 AF XY: 0.0000179 AC XY: 13AN XY: 724286
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152212Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74368
ClinVar
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:5Other:1
Likely 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 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
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 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pendred syndrome Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 24, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2003 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 721 of the SLC26A4 protein (p.Thr721Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with enlarged vestibular aqueduct and hearing loss (PMID: 10190331, 26763877, 28964290). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4826). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 20826203). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 16, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2021 | Published functional studies demonstrate a damaging effect; variant protein is retained in the cytoplasm leading to the loss of normal anion transporter activity (Ishihara et al., 2010); This variant is associated with the following publications: (PMID: 15905611, 32447495, 31589614, 30275481, 31541171, 31599023, 31427586, 12112665, 18813951, 26763877, 24599119, 20826203, 23185506, 17949297, 11748854, 15355436, 21704276, 27176802, 20597900, 29871341, 28964290, 10190331, 12676893, 26004784, 14508505, 25266519, 17443271) - |
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 29, 2016 | The p.Thr721Met variant in SLC26A4 has been reported in at least 7 individuals f rom 5 families with hearing loss and enlarged vestibular aqueduct (EVA) or Pendr ed Syndrome (Chen 2011, Ishihara 2010, Kahrizi 2009, Lopez-Bigas 2001, Usami 199 9). Individuals were either homozygous (2 families) or heterozygous with anoth er pathogenic variant (3 families). Compound heterozygous variants were confir med to be in trans in at least one family. In addition, a study showed that the Thr721Met variant impacts protein function (Ishihara 2010). This variant has b een identified in 5/11486 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908363); however, this freque ncy is low enough to be consistent with a recessive carrier frequency. In summa ry, this variant meets our criteria to be classified as pathogenic for autosomal recessive hearing loss with EVA or Pendred syndrome. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at