chr7-107661643-T-C

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PVS1PS1_ModeratePM2PP5_Very_Strong

The NM_000441.2(SLC26A4):ā€‹c.2T>Cā€‹(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 0.000145 in 1,562,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.000079 ( 0 hom., cov: 32)
Exomes š‘“: 0.00015 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 start_lost

Scores

4
5
7

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

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 20 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000441.2 (SLC26A4) was described as [Pathogenic] in ClinVar as 1185667
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-107661643-T-C is Pathogenic according to our data. Variant chr7-107661643-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 43553.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107661643-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SLC26A4NM_000441.2 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/21 ENST00000644269.2
SLC26A4-AS1NR_028137.1 linkuse as main transcriptn.156A>G non_coding_transcript_exon_variant 1/2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SLC26A4ENST00000644269.2 linkuse as main transcriptc.2T>C p.Met1? start_lost 2/21 NM_000441.2 P1O43511-1
SLC26A4-AS1ENST00000668981.1 linkuse as main transcriptn.216A>G non_coding_transcript_exon_variant 1/2

Frequencies

GnomAD3 genomes
AF:
0.0000788
AC:
12
AN:
152258
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000694
AC:
12
AN:
172798
Hom.:
0
AF XY:
0.0000846
AC XY:
8
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:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000152
AC:
214
AN:
1410366
Hom.:
0
Cov.:
30
AF XY:
0.000129
AC XY:
90
AN XY:
698144
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000260
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:
0.000190
Gnomad4 OTH exome
AF:
0.0000850
GnomAD4 genome
AF:
0.0000788
AC:
12
AN:
152258
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74394
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000150
Hom.:
0
Bravo
AF:
0.0000907
ExAC
AF:
0.0000260
AC:
3

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:5
Pathogenic, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxAug 31, 2023Published functional studies demonstrate that variant results in protein retention in the endoplasmic reticulum (Choi et al., 2009); This variant is associated with the following publications: (PMID: 27997596, 25372295, 19509082, 20128824, 15099345, 14679580, 24224479, 28780564, 21961810, 16950989, 23965030, 21704276, 19204907, 31589614, 34062854) -
Pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeJan 30, 2024This 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 (rs111033302, gnomAD 0.02%). Disruption of the initiator codon has been observed in individual(s) with nonsyndromic sensorineural hearing loss and enlargement of vestibular aqueduct (PMID: 19204907, 19509082, 21961810, 23965030, 25372295, 27997596). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 43553). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. 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. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 07, 2021- -
Pendred syndrome Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 11, 2019This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as pathogenic [PMID 14679580, 19204907, 21961810, 24224479] -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 06, 2023Variant summary: SLC26A4 c.2T>C (p.Met1Thr) 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 damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 172798 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in SLC26A4 causing Pendred Syndrome (6.9e-05 vs 0.0035), allowing no conclusion about variant significance. c.2T>C has been reported in the literature in individuals affected with Enlargement of the Vestibular aqueduct and Hearing loss, usually associated with Pendred Syndrome( Example: Alber_2006, Choi_2009, Siem_2010, Sloan-Heggen_2016, Smits_2022, Gardner_2006 etc). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Choi_2009) indicating the protein was retained within the endoplasmic reticulum with no surface expression. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:4
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsJan 03, 2020This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitterclinical testingJohns Hopkins Genomics, Johns Hopkins UniversityJun 21, 2023This SLC26A4 variant (rs111033302) is rare (<0.1%) in a large population dataset (gnomAD: 16/204190 total alleles; MAF 0.008%; no homozygotes) and has been reported in ClinVar. This variant alters the initiation codon and is predicted to result either in absence of the protein or alteration of the encoded protein due to translation initiation at a downstream methionine codon. In vitro functional studies of p.Met1Thr using transfected cells showed the protein was retained within the endoplasmic reticulum with no surface expression. This SLC26A4 variant has been reported in unrelated individuals with hearing loss and EVA, usually in a compound heterozygous state with a different pathogenic variant. We consider c.2T>C (p.Met1Thr) to be pathogenic for DFNB4. -
Pathogenic, criteria provided, single submitterclinical testingNeurogenetic Laboratory, Second Faculty of Medicine, Charles UniversityMar 30, 2021- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
SLC26A4-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesJan 19, 2023The SLC26A4 c.2T>C variant is predicted to disrupt the translation initiation site (Start Loss). This variant has been reported in individuals with autosomal recessive Pendred syndrome or nonsyndromic enlarged vestibular aqueduct (NSEVA) (reported as "M1T" in Prasad et al. 2004. PubMed ID: 14679580; Choi et al. 2009. PubMed ID: 19204907; Ladsous et al. 2014. PubMed ID: 24224479). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107302088-T-C). This variant has been classified as pathogenic by multiple independent submitters to the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/43553). Given all the evidence, we interpret c.2T>C (p.Met1?) as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterOct 03, 2022PVS1_Strong, PS3, PM3_Strong -
Rare genetic deafness Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineNov 22, 2017The c.2T>C (p.Met1?) variant in SLC26A4 has been reported in at least 6 individu als with hearing loss and EVA, all of whom were compound heterozygous (Shears 20 04, Gardner 2006, Dai 2009, Choi 2009, Huang 2011, Ladsous 2014, LMM data). It h as been identified in 0.01% (14/87438) of European chromosomes by the Genome Agg regation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs111033302). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency for recessive hearing loss . This variant affects the translation initiation start codon (ATG) and is there fore predicted to disrupt translation. In vitro functional studies provide some evidence that the c.2T>C variant may impact protein function (Choi 2009). Additi onally, a different variant in the translation initiation start codon (c.3G>C) h as also been reported in an individual with hearing loss and EVA, supporting tha t changes to this codon are not tolerated. In summary, this variant meets crite ria to be classified as pathogenic for hearing loss in an autosomal recessive ma nner based on the predicted impact of the variant and multiple occurrences with pathogenic SLC26A4 variants in individuals with hearing loss. ACMG/AMP Criteria applied: PVS1; PM3_VeryStrong; PP4. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.38
CADD
Benign
23
DANN
Benign
0.95
DEOGEN2
Benign
0.15
T;T;T
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.90
.;D;D
M_CAP
Pathogenic
0.95
D
MetaRNN
Uncertain
0.65
D;D;D
MetaSVM
Uncertain
0.23
D
MutationTaster
Benign
0.97
D
PROVEAN
Benign
-1.2
N;.;N
REVEL
Uncertain
0.62
Sift
Uncertain
0.0080
D;.;D
Sift4G
Pathogenic
0.0
D;.;D
Polyphen
0.089
B;B;.
Vest4
0.94
MVP
0.97
ClinPred
0.58
D
GERP RS
3.8
Varity_R
0.56
gMVP
0.57

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: rs111033302; hg19: chr7-107302088; API