7-107661643-T-G

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.2T>Gā€‹(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000709 in 1,410,366 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: not found (cov: 32)
Exomes š‘“: 7.1e-7 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 start_lost

Scores

5
5
6

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 2.90
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)

Genome browser will be placed here

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 7-107661643-T-G is Pathogenic according to our data. Variant chr7-107661643-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2136582.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.2T>G p.Met1? start_lost Exon 2 of 21 ENST00000644269.2 NP_000432.1 O43511-1
SLC26A4-AS1NR_028137.1 linkn.156A>C 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.2T>G p.Met1? start_lost Exon 2 of 21 NM_000441.2 ENSP00000494017.1 O43511-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000579
AC:
1
AN:
172798
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
94532
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000738
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
7.09e-7
AC:
1
AN:
1410366
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
698144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000265
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.0000260
AC:
3

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:2
Mar 22, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Experimental studies have shown that disruption of the initiator codon affects SLC26A4 function (PMID: 19204907). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 2136582). Disruption of the initiator codon has been observed in individuals with SLC26A4-related conditions (PMID: 17876604, 19204907, 21961810, 27997596). This variant is present in population databases (rs111033302, gnomAD 0.008%). This sequence change affects the initiator methionine of the SLC26A4 mRNA. The next in-frame methionine is located at codon 21. -

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

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.34
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.15
T;T;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.15
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.98
D;D;D
MetaSVM
Uncertain
0.20
D
PROVEAN
Benign
-1.1
N;.;N
REVEL
Uncertain
0.57
Sift
Uncertain
0.0020
D;.;D
Sift4G
Pathogenic
0.0
D;.;D
Polyphen
0.0
B;B;.
Vest4
0.90
MutPred
0.98
Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);Gain of methylation at M1 (P = 0.0082);
MVP
0.92
ClinPred
0.93
D
GERP RS
3.8
Varity_R
0.89
gMVP
0.70

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: rs111033302; hg19: chr7-107302088; COSMIC: COSV55916531; API