7-107702050-T-C

Position:

• chr7-107702050-T-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000441.2(SLC26A4):​c.2027T>C​(p.Leu676Pro) variant causes a missense change. 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L676Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.78

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain STAS (size 194) in uniprot entity S26A4_HUMAN there are 17 pathogenic changes around while only 4 benign (81%) in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107702050-T-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 7-107702050-T-C is Pathogenic according to our data. Variant chr7-107702050-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1515298.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2027T>C	p.Leu676Pro	missense_variant	17/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2027T>C	p.Leu676Pro	missense_variant	17/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.314T>C		non_coding_transcript_exon_variant	2/6	5
SLC26A4	ENST00000644846.1	n.737T>C		non_coding_transcript_exon_variant	7/10			ENSP00000494344.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 14, 2020

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Leu676 amino acid residue in SLC26A4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12676893, 14715652, 21961810, 18310264). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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) performed at Invitae indicates that this missense variant is expected to disrupt SLC26A4 protein function. This variant has not been reported in the literature in individuals with SLC26A4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 676 of the SLC26A4 protein (p.Leu676Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	.;T
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	3.1	M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.4	D;.
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;D
Vest4		0.91
MutPred		0.92		Loss of stability (P = 0.0131);Loss of stability (P = 0.0131);
MVP		0.99
MPC		0.074
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-107342495; COSMIC: COSV99706929; COSMIC: COSV99706929;