NM_000441.2:c.397T>A

Variant names:

• chr7-107672230-T-A
• rs121908365
• NM_000441.2:c.397T>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.397T>A​(p.Ser133Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000279 in 1,435,244 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 (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.49

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant 7-107672230-T-A is Pathogenic according to our data. Variant chr7-107672230-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.397T>A	p.Ser133Thr	missense_variant	Exon 4 of 21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.397T>A	p.Ser133Thr	missense_variant	Exon 4 of 21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000440056.1	c.*4T>A		downstream_gene_variant		4		ENSP00000394760.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000279 AC: 4 AN: 1435244 Hom.: 0 Cov.: 26 AF XY: 0.00000279 AC XY: 2 AN XY: 715846

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: 0.00000276

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:2

May 03, 2017

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1 Other:1

Aug 20, 2019

National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center

Significance: Affects

Review Status: no assertion criteria provided

Collection Method: in vitro;literature only

in vitro experiment -

Aug 01, 2020

King Laboratory, University of Washington

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Analysis of patient-derived RNA indicates that SLC26A4 c.397T>A leads to skipping of exon 4 (111bp) in message, with loss of aa 102-138 of TM1 and TM2 (Abu Rayyan 2020). The variant is homozygous in a Palestinian child with severe to profound pre-lingual hearing loss (Abu Rayyan 2020). It is absent from 1300 Palestinian controls and from gnomAD v2.1.1. -

not provided Pathogenic:1

Feb 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Pendred syndrome (PMID: 11919333, 12788906). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4834). 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. Studies have shown that this missense change results in skipping of exon 4, but is expected to preserve the integrity of the reading-frame (PMID: 32747562). For these reasons, this variant has been classified as Pathogenic. This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 133 of the SLC26A4 protein (p.Ser133Thr). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M;M
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-2.6	D;.
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.060	T;.
Polyphen		1.0	D;D
Vest4		0.99
MutPred		0.85		Gain of glycosylation at S133 (P = 0.0387);Gain of glycosylation at S133 (P = 0.0387);
MVP		0.98
MPC		0.076
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.88

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: rs121908365; hg19: chr7-107312675;