7-107690200-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1226G>C​(p.Arg409Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R409C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

16
2
1

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.75
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1
In a topological_domain Extracellular (size 15) in uniprot entity S26A4_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000441.2
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-107690199-C-T is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant 7-107690200-G-C is Pathogenic according to our data. Variant chr7-107690200-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 43497.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.1226G>C p.Arg409Pro missense_variant Exon 10 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.1226G>C p.Arg409Pro missense_variant Exon 10 of 21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151988
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:
0.00
Gnomad SAS
AF:
0.000208
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000797
AC:
2
AN:
250826
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135534
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1459874
Hom.:
0
Cov.:
30
AF XY:
0.00000413
AC XY:
3
AN XY:
726354
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151988
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
May 22, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:1
Jan 29, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 409 of the SLC26A4 protein (p.Arg409Pro). This variant is present in population databases (rs111033305, gnomAD 0.006%). This missense change has been observed in individual(s) with deafness (PMID: 12676893, 25266519). ClinVar contains an entry for this variant (Variation ID: 43497). 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%. This variant disrupts the p.Arg409 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11919333, 16053392, 19786220, 20597900, 24224479). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Hearing loss, autosomal recessive Pathogenic:1
-
University of Washington Center for Mendelian Genomics, University of Washington
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Rare genetic deafness Pathogenic:1
Nov 05, 2009
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Likely pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1
Dec 29, 2021
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PP3, PM1, PM2, PM3, PM5 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
33
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.90
D;D
Eigen
Pathogenic
0.98
Eigen_PC
Pathogenic
0.89
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Pathogenic
0.98
.;D
M_CAP
Pathogenic
0.59
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.6
H;H
PrimateAI
Pathogenic
0.79
T
PROVEAN
Pathogenic
-6.7
D;.
REVEL
Pathogenic
0.97
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0
D;.
Polyphen
1.0
D;D
Vest4
1.0
MutPred
0.97
Gain of glycosylation at T410 (P = 0.0263);Gain of glycosylation at T410 (P = 0.0263);
MVP
1.0
MPC
0.075
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.98
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

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: rs111033305; hg19: chr7-107330645; API