7-107661644-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePS1_ModeratePM2PP5_Very_Strong

The NM_000441.2(SLC26A4):ā€‹c.3G>Cā€‹(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000192 in 1,562,516 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 start_lost

Scores

5
6
5

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 3.97
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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 60 CDS bases. Genomic position: 107661701. Lost 0.026 part of the original CDS.
PS1
Another start lost variant in NM_000441.2 (SLC26A4) was described as [Pathogenic] in Lovd
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-107661644-G-C is Pathogenic according to our data. Variant chr7-107661644-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188721.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.3G>C p.Met1? start_lost Exon 2 of 21 ENST00000644269.2 NP_000432.1 O43511-1
SLC26A4-AS1NR_028137.1 linkn.155C>G non_coding_transcript_exon_variant Exon 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SLC26A4ENST00000644269.2 linkc.3G>C p.Met1? start_lost Exon 2 of 21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152276
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:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000142
AC:
2
AN:
1410240
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
698074
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000183
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152276
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74394
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:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Pendred syndrome Pathogenic:4
Mar 16, 2014
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: literature only

- -

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

- -

Oct 09, 2023
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Feb 08, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: SLC26A4 c.3G>C (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31384 control chromosomes (gnomAD). c.3G>C has been reported in the literature in two compound heterozygous individuals (siblings) affected with Pendred Syndrome in one family (Banghova_2007). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite this variant as pathogenic (n=2) and likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

not provided Pathogenic:2
Dec 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. This variant is present in population databases (rs786204426, gnomAD 0.007%). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). ClinVar contains an entry for this variant (Variation ID: 188721). For these reasons, this variant has been classified as Pathogenic. -

Jul 17, 2019
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17876604) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.37
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.14
T;T;T
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.085
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Pathogenic
0.90
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Uncertain
0.0016
D
PROVEAN
Benign
-0.92
N;.;N
REVEL
Uncertain
0.56
Sift
Uncertain
0.026
D;.;D
Sift4G
Pathogenic
0.0
D;.;D
Polyphen
0.020
B;B;.
Vest4
0.90
MutPred
1.0
Loss of glycosylation at P4 (P = 0.4565);Loss of glycosylation at P4 (P = 0.4565);Loss of glycosylation at P4 (P = 0.4565);
MVP
0.85
ClinPred
0.99
D
GERP RS
3.8
Varity_R
0.47
gMVP
0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs786204426; hg19: chr7-107302089; API