Genetic Variant SLC26A4:p.Leu50Pro (chr7-107661790-T-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_000441.2(SLC26A4):c.149T>C(p.Leu50Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,386,172 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 Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L50L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 3.27

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.149T>C	p.Leu50Pro	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.9A>G		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.149T>C	p.Leu50Pro	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1386172

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

684154

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31580

American (AMR)

AF:

0.00

AC:

AN:

35720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25146

East Asian (EAS)

AF:

0.00

AC:

AN:

35782

South Asian (SAS)

AF:

0.0000253

AC:

AN:

79182

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4778

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078896

Other (OTH)

AF:

0.00

AC:

AN:

57816

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pendred syndrome

Uncertain:1

Feb 07, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Uncertain

0.074

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;D;T

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.65

.;T;T

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.86

D;D;D

MetaSVM

Uncertain

-0.14

MutationAssessor

Uncertain

2.5

M;M;.

PhyloP100

3.3

PrimateAI

Uncertain

0.53

PROVEAN

Pathogenic

-5.1

D;.;D

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0020

D;.;D

Sift4G

Uncertain

0.0030

D;.;D

Polyphen

0.86

P;P;.

Vest4

0.62

MutPred

0.65

Gain of glycosylation at L50 (P = 0.0131);Gain of glycosylation at L50 (P = 0.0131);Gain of glycosylation at L50 (P = 0.0131);

MVP

0.96

MPC

0.043

ClinPred

0.99

GERP RS

4.2

Varity_R

0.90

gMVP

0.89

Mutation Taster

=15/85

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

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over