7-107672245-G-C

Position:

• chr7-107672245-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.412G>C​(p.Val138Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000142 in 1,412,088 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V138F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.29

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107672245-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929
• PP5: Variant 7-107672245-G-C is Pathogenic according to our data. Variant chr7-107672245-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.412G>C	p.Val138Leu	missense_variant	4/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.412G>C	p.Val138Leu	missense_variant	4/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000440056.1	c.*19G>C		downstream_gene_variant		4		ENSP00000394760.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000142 AC: 2 AN: 1412088 Hom.: 0 Cov.: 24 AF XY: 0.00000283 AC XY: 2 AN XY: 705516

Gnomad4 AFR exome AF: 0.0000308

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is not observed in the gnomAD v2.1.1 dataset. Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 19645628). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.82; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change (ClinVar ID: VCV000556058) and a different missense change at the same codon (p.Val138Phe / ClinVar ID: VCV000004835) have been previously reported as pathogenic/likely pathogenic with strong evidence. Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	May 31, 2023	- -

Pendred syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 10, 2018

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 03, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Val138 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9618166, 11932316, 12788906, 21551164, 23273637, 24224479, 26969326). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 19645628). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. ClinVar contains an entry for this variant (Variation ID: 556058). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 18665027, 19645628, 25488846). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 138 of the SLC26A4 protein (p.Val138Leu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	N;.
REVEL	Pathogenic	0.82
Sift	Uncertain	0.028	D;.
Sift4G	Uncertain	0.056	T;.
Polyphen		0.97	D;D
Vest4		0.80
MutPred		0.86		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);
MVP		0.99
MPC		0.016
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.48
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: rs111033199; hg19: chr7-107312690;