NM_000441.2:c.87G>T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1PM1PM2PM5PP2PP5

The NM_000441.2(SLC26A4):c.87G>T(p.Glu29Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000214 in 1,404,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E29G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 1.78

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PS1

Transcript NM_000441.2 (SLC26A4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain 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 chr7-107661727-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 552271.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.

PP5

Variant 7-107661728-G-T is Pathogenic according to our data. Variant chr7-107661728-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 554998.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.87G>T	p.Glu29Asp	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.71C>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.87G>T	p.Glu29Asp	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000214

AC:

AN:

1404860

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

694440

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32330

American (AMR)

AF:

0.00

AC:

AN:

37410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25302

East Asian (EAS)

AF:

0.00

AC:

AN:

37048

South Asian (SAS)

AF:

0.0000250

AC:

AN:

80142

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42010

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5526

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086576

Other (OTH)

AF:

0.00

AC:

AN:

58516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.408

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Nov 09, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22285650) -

Pendred syndrome

Uncertain:1

Nov 10, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Apr 22, 2025

Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A heterozygous missense variant in exon 2 of the SLC26A4 gene that results in the amino acid substitution of Aspartic acid for Glutamic acid at codon 29 (p.Glu29Asp) was detected. The observed variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomAD (v2.1) and topmed databases. The in-silico predictions of the variant are damaging by SIFT and LRT. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.33

T;T;T

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.54

.;T;T

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Uncertain

-0.032

MutationAssessor

Benign

2.0

M;M;.

PhyloP100

1.8

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.9

N;.;N

REVEL

Uncertain

0.60

Sift

Benign

0.10

T;.;T

Sift4G

Benign

0.068

T;.;T

Polyphen

0.026

B;B;.

Vest4

0.76

MutPred

0.75

Loss of helix (P = 0.079);Loss of helix (P = 0.079);Loss of helix (P = 0.079);

MVP

0.91

MPC

0.012

ClinPred

0.55

GERP RS

2.3

Varity_R

0.16

gMVP

0.69

Mutation Taster

=27/73

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over