rs200102493

chr7-107661669-C-Achr7-107661669-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000441.2(SLC26A4):c.28C>A(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,570,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:1
• Conservation: PhyloP100: 1.56

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-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0062066913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.28C>A	p.Pro10Thr	missense_variant	2/21	ENST00000644269.2
SLC26A4-AS1	NR_028137.1	n.130G>T		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.28C>A	p.Pro10Thr	missense_variant	2/21		NM_000441.2	P1
SLC26A4-AS1	ENST00000668981.1	n.190G>T		non_coding_transcript_exon_variant	1/2

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152274 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00231

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000160 AC: 29 AN: 181450 Hom.: 0 AF XY: 0.000101 AC XY: 10 AN XY: 99102

Gnomad AFR exome AF: 0.00217

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000709

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000508 AC: 72 AN: 1417634 Hom.: 0 Cov.: 31 AF XY: 0.0000413 AC XY: 29 AN XY: 702236

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.000178

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: 0.00

Gnomad4 OTH exome AF: 0.0000848

GnomAD4 genome AF: 0.000669 AC: 102 AN: 152392 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74526

Gnomad4 AFR AF: 0.00233

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.0000297 Hom.: 0

Bravo AF: 0.000748

ESP6500AA AF: 0.00121 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000937 AC: 11

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 30, 2022	The p.Pro10Thr variant in SLC26A4 has been reported in three individuals with enlarged vestibular aqueduct and in 1 individual with hearing loss (EVA; Madden 2007 PMID: 17309986, Greinwald 2013 PMID: 23401162, LMM data). One of these individuals also carried two additional variants in the SLC26A4 gene and it is unclear which of these variants, if any, are responsible for the EVA. It has also been identified in 0.2% (96/41480) of African chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43550). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the computational predictions and the presence of this variant in the general population, we would lean towards a more likely benign role. ACMG/AMP Criteria applied: BS1_P. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 06, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 01, 2022	- -

Pendred syndrome Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 03, 2017	- -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

SLC26A4-related condition Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 10, 2023

The SLC26A4 c.28C>A variant is predicted to result in the amino acid substitution p.Pro10Thr. This variant was reported in an individual with enlarged vestibular aqueduct along with two other potentially pathogenic variants (described as P1028C>A, Madden. 2007. PubMed ID: 17309986) and has been reported as likely benign by an expert panel (Table S3, Azaiez. 2018. PubMed ID: 30245029). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107302114-C-A). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	18
Dann	Benign	0.96
DEOGEN2	Benign	0.12	T;T;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.68	D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.0062	T;T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	0.0	N;N;.
MutationTaster	Benign	0.94	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.0	N;.;N
REVEL	Uncertain	0.52
Sift	Benign	0.29	T;.;T
Sift4G	Benign	0.23	T;.;T
Polyphen		0.039	B;B;.
Vest4		0.18
MVP		0.82
MPC		0.012
ClinPred		0.013	T
GERP RS		3.2
Varity_R		0.056
gMVP		0.52

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: rs200102493; hg19: chr7-107302114;