rs876657723

Positions:

• chr7-107710187-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.2224del​(p.Ile742PhefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SLC26A4 NM_000441.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 2.52

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107710187-CA-C is Pathogenic according to our data. Variant chr7-107710187-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 228397.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.2224del	p.Ile742PhefsTer2	frameshift_variant	19/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2224del	p.Ile742PhefsTer2	frameshift_variant	19/21		NM_000441.2	ENSP00000494017	P1
SLC26A4	ENST00000492030.2	n.410del		non_coding_transcript_exon_variant	4/6	5
SLC26A4	ENST00000644846.1	c.*126del		3_prime_UTR_variant, NMD_transcript_variant	8/10			ENSP00000494344

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 18, 2019

For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). This variant has not been reported in the literature in individuals with SLC26A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 228397). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ile742Phefs*2) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. -

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 26, 2015

The p.Ile742fs variant in SLC26A4 has not been previously reported in individual s with hearing loss or Pendred syndrome and it was absent from large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 742 and lead to a premature termination codon 2 a mino acids downstream, which is predicted to lead to a truncated or absent prote in. In summary, this variant meets our criteria to be classified as pathogenic f or hearing loss in an autosomal recessive manner based on its predicted impact. -

Computational scores

Source: dbNSFP v4.3

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: rs876657723; hg19: chr7-107350632;