Genetic Variant SLC26A4:p.Ser23Leu (chr7-107661709-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PM1PM2PP2BP4

The NM_000441.2(SLC26A4):c.68C>T(p.Ser23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S23S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.09

Publications

7 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: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 11 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;

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.39405426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.68C>T	p.Ser23Leu	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.90G>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.68C>T	p.Ser23Leu	missense_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:

1415600

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

700714

African (AFR)

AF:

0.00

AC:

AN:

32674

American (AMR)

AF:

0.00

AC:

AN:

38938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25430

East Asian (EAS)

AF:

0.00

AC:

AN:

37724

South Asian (SAS)

AF:

0.00

AC:

AN:

80998

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42854

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5572

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092540

Other (OTH)

AF:

0.00

AC:

AN:

58870

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.48

T;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.063

FATHMM_MKL

Uncertain

0.76

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Uncertain

0.21

MutationAssessor

Uncertain

2.0

M;M;.

PhyloP100

3.1

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-2.8

D;.;D

REVEL

Uncertain

0.34

Sift

Benign

0.13

T;.;T

Sift4G

Benign

0.19

T;.;T

Polyphen

0.32

B;B;.

Vest4

0.35

MutPred

0.38

Loss of phosphorylation at S23 (P = 0.0298);Loss of phosphorylation at S23 (P = 0.0298);Loss of phosphorylation at S23 (P = 0.0298);

MVP

0.90

MPC

0.014

ClinPred

0.85

GERP RS

4.2

Varity_R

0.33

gMVP

0.55

Mutation Taster

=60/40

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over