Genetic Variant SLC26A4:p.Met1? (chr7-107661642-A-T) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000441.2(SLC26A4):c.1A>T(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC26A4
NM_000441.2 initiator_codon

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 3.40

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 links:

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

SLC26A4-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 107661702. Lost 0.026 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-107661642-A-T is Pathogenic according to our data. Variant chr7-107661642-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3777243.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.157T>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1410262

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698088

African (AFR)

AF:

0.00

AC:

AN:

32668

American (AMR)

AF:

0.00

AC:

AN:

38450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25414

East Asian (EAS)

AF:

0.00

AC:

AN:

37730

South Asian (SAS)

AF:

0.00

AC:

AN:

80826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5596

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091544

Other (OTH)

AF:

0.00

AC:

AN:

58816

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Apr 08, 2025

Hereditary Deafness Genetic Testing Group, The First Affiliated Hospital of Zhengzhou University

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

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.13

T;T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.98

D;D;D

MetaSVM

Uncertain

-0.11

PhyloP100

3.4

PROVEAN

Benign

-0.76

N;.;N

REVEL

Uncertain

0.52

Sift

Benign

0.049

D;.;D

Sift4G

Pathogenic

0.0

D;.;D

Polyphen

0.0

B;B;.

Vest4

0.77

MutPred

0.99

Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);Gain of stability (P = 0.0485);

MVP

0.89

ClinPred

0.98

GERP RS

2.6

Varity_R

0.37

gMVP

0.39

Mutation Taster

=24/176

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over