chr7-107689130-C-T

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM2PP2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1079C>T​(p.Ala360Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,082 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 Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

SLC26A4
NM_000441.2 missense

Scores

9
8
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 4.32

Publications

26 publications found
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 Gene-Disease associations (from GenCC):
  • autosomal recessive nonsyndromic hearing loss 4
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
  • Pendred syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
  • athyreosis
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • thyroid hypoplasia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hearing loss, autosomal recessive
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_000441.2
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 7-107689130-C-T is Pathogenic according to our data. Variant chr7-107689130-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 188793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107689130-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 188793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107689130-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 188793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107689130-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 188793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107689130-C-T is described in CliVar as Pathogenic/Likely_pathogenic. Clinvar id is 188793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SLC26A4NM_000441.2 linkc.1079C>T p.Ala360Val missense_variant Exon 9 of 21 ENST00000644269.2 NP_000432.1 O43511-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkc.1079C>T p.Ala360Val missense_variant Exon 9 of 21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152082
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152082
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74282
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41414
American (AMR)
AF:
0.00
AC:
0
AN:
15250
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.000193
AC:
1
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4824
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10580
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.575
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pendred syndrome Pathogenic:3
May 21, 2014
Counsyl
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Sep 16, 2020
Natera, Inc.
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Sep 05, 2021
Genome-Nilou Lab
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3
Feb 26, 2019
Genetic Testing Center for Deafness, Department of Otolaryngology Head & Neck Surgery, Institute of Otolaryngology, Chinese PLA General Hospital
Significance:Likely pathogenic
Review Status:no assertion criteria provided
Collection Method:case-control

- -

Sep 18, 2023
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Sep 05, 2021
Genome-Nilou Lab
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:3
Jan 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 360 of the SLC26A4 protein (p.Ala360Val). This variant is present in population databases (rs786204474, gnomAD 0.06%). This missense change has been observed in individual(s) with hearing loss (PMID: 17697873, 21961810, 23838540, 26252218, 26969326). 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: 188793). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SLC26A4 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

Nov 11, 2022
Revvity Omics, Revvity
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 14, 2023
GeneDx
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Published functional studies demonstrate this variant impairs SLC26A4 protein localization and function (Yuan et al., 2012); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30842343, 23185506, 26969326, 23838540, 21154317, 17697873, 21961810, 26252218, 27771369, 30275481, 31541171, 24612839, 24341454, 23151025, 33199029, 32447495, 36362242, 35982127, 34416374, 33907123, 32658404) -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2
Oct 14, 2022
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:research

- -

-
Juno Genomics, Hangzhou Juno Genomics, Inc
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

PM2_Supporting+PP3+PM3_VeryStrong -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.61
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D;D
Eigen
Uncertain
0.67
Eigen_PC
Pathogenic
0.68
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
.;D
M_CAP
Pathogenic
0.47
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Benign
1.5
L;L
PhyloP100
4.3
PrimateAI
Uncertain
0.68
T
PROVEAN
Uncertain
-3.1
D;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0030
D;.
Polyphen
1.0
D;D
Vest4
0.90
MutPred
0.94
Loss of glycosylation at S355 (P = 0.2019);Loss of glycosylation at S355 (P = 0.2019);
MVP
0.98
MPC
0.075
ClinPred
0.98
D
GERP RS
5.6
Varity_R
0.68
gMVP
0.95
Mutation Taster
=17/83
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs786204474; hg19: chr7-107329575; API