rs1345175795

Positions:

• chr7-107663358-C-G
• chr7-107663358-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000441.2(SLC26A4):​c.227C>G​(p.Pro76Arg) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.227C>G	p.Pro76Arg	missense_variant	3/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.227C>G	p.Pro76Arg	missense_variant	3/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000440056.1	c.227C>G	p.Pro76Arg	missense_variant	3/4	4		ENSP00000394760.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 11, 2018

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces proline with arginine at codon 76 of the SLC26A4 protein (p.Pro76Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with SLC26A4-related disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Other missense substitutions at this codon (p.Pro76Leu and p.Pro76Ser) have been reported in individuals affected with hearing loss and enlarged vestibular aqueduct (PMID: 17718863, 17851929, 25372295, 27792752). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Uncertain	-0.028	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.36	T
PROVEAN	Pathogenic	-6.7	D;.;D
REVEL	Pathogenic	0.75
Sift	Uncertain	0.019	D;.;D
Sift4G	Uncertain	0.047	D;.;D
Polyphen		0.96	D;D;.
Vest4		0.58
MutPred		0.81		Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);Gain of MoRF binding (P = 0.0025);
MVP		0.93
MPC		0.076
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.68
gMVP		0.83

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: rs1345175795; hg19: chr7-107303803;