rs431905517

Positions:

• chr7-103413015-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_198999.3(SLC26A5):​c.390A>C​(p.Arg130Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,454,312 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC26A5 NM_198999.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.188

Genes affected

SLC26A5 (HGNC:9359): (solute carrier family 26 member 5) This gene encodes a member of the SLC26A/SulP transporter family. The protein functions as a molecular motor in motile outer hair cells (OHCs) of the cochlea, inducing changes in cell length that act to amplify sound levels. The transmembrane protein is an incomplete anion transporter, and does not allow anions to cross the cell membrane but instead undergoes a conformational change in response to changes in intracellular Cl- levels that results in a change in cell length. The protein functions at microsecond rates, which is several orders of magnitude faster than conventional molecular motor proteins. Mutations in this gene are potential candidates for causing neurosensory deafness. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.883
• PP5: Variant 7-103413015-T-G is Pathogenic according to our data. Variant chr7-103413015-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 97020.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-103413015-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A5	NM_198999.3	c.390A>C	p.Arg130Ser	missense_variant	5/20	ENST00000306312.8	NP_945350.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A5	ENST00000306312.8	c.390A>C	p.Arg130Ser	missense_variant	5/20	1	NM_198999.3	ENSP00000304783	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1454312 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723972

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.05e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 61 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 28, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	.;.;.;.;D;.;D;D;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.098
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D;D;.;D;D;D;.;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;M;M;.;.;M
MutationTaster	Benign	0.99	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.9	D;D;D;D;D;D;.;D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D
Polyphen		0.53	P;D;D;.;B;.;.;.;.
Vest4		0.63
MutPred		0.77		Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);Gain of glycosylation at S133 (P = 0.1573);
MVP		0.86
MPC		0.23
ClinPred		0.99	D
GERP RS		0.31
Varity_R		0.81
gMVP		0.79

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

Other links and lift over

dbSNP: rs431905517; hg19: chr7-103053462;