rs121908365

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr7-107672230-T-A
• chr7-107672230-T-C

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S133P) has been classified 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:5 O:1
• Conservation: PhyloP100: 7.49
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• autosomal recessive nonsyndromic hearing loss 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• Pendred syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
• athyreosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• thyroid hypoplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PM1: In a hotspot region, there are 16 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain 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 chr7-107672230-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1502303.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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

African (AFR) AF: 0.00 AC: 0 AN: 32908

American (AMR) AF: 0.00 AC: 0 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 85744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5712

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1087872

Other (OTH) AF: 0.00 AC: 0 AN: 59444

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:3

Mar 07, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SLC26A4 c.397T>A (p.Ser133Thr) results in a conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251354 control chromosomes (gnomAD). c.397T>A has been reported in the literature in individuals affected with Pendred Syndrome (Fugazzola_2002, Borck_2003). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected the SLC26A4 protein function (Wasano_2020). ClinVar contains an entry for this variant (Variation ID: 4834). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 03, 2017

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

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
PhyloP100		7.5
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
Mutation Taster		=7/93	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121908365; hg19: chr7-107312675;