rs201562855
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000441.2(SLC26A4):c.1174A>T(p.Asn392Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,002 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
SLC26A4
NM_000441.2 missense
NM_000441.2 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 8.37
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
?
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000441.2
PM2
?
Very rare variant in population databases, with high coverage;
PP3
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MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
?
Variant 7-107690148-A-T is Pathogenic according to our data. Variant chr7-107690148-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 446453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107690148-A-T is described in Lovd as [Likely_pathogenic]. Variant chr7-107690148-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC26A4 | NM_000441.2 | c.1174A>T | p.Asn392Tyr | missense_variant | 10/21 | ENST00000644269.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC26A4 | ENST00000644269.2 | c.1174A>T | p.Asn392Tyr | missense_variant | 10/21 | NM_000441.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251084Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135676
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GnomAD4 exome AF: 0.00000343 AC: 5AN: 1459716Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726346
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152286Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74468
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 29, 2024 | - - |
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 | - - |
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 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2018 | The N392Y missense variant has been previously reported in both the homozygous and compound heterozygous state in association with SLC26A4-related disorders (Huang et al., 2011; Luo et al., 2017; Reyes et al., 2009). Functional studies report that N392Y resulted in the change of intracellular localization of the protein and the loss of anion transporter activity (Ishihara et al., 2010). The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. In summary, we consider this to be a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 06, 2023 | This sequence change replaces asparagine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 392 of the SLC26A4 protein (p.Asn392Tyr). This variant is present in population databases (rs201562855, gnomAD 0.006%). This missense change has been observed in individual(s) with nonsyndromic hearing loss and enlargement of the vestibular aqueduct (PMID: 17718863, 19786220, 21961810). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 446453). 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. - |
Pendred syndrome Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 22, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;.
Polyphen
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at