rs145467740

Positions:

• chr7-107689120-G-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. BA1 PP3

This summary comes from the ClinGen Evidence Repository: The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA132654/MONDO:0010134/005

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:7
• Conservation: PhyloP100: 7.13

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 Benign. Variant got -7 ACMG points.

• PP3: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1069G>A	p.Ala357Thr	missense_variant	9/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1069G>A	p.Ala357Thr	missense_variant	9/21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 244 AN: 152116 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000434 AC: 109 AN: 251198 Hom.: 0 AF XY: 0.000339 AC XY: 46 AN XY: 135750

Gnomad AFR exome AF: 0.00511

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000167 AC: 244 AN: 1461614 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 117 AN XY: 727118

Gnomad4 AFR exome AF: 0.00454

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000432

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152234 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74422

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.000982

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000368 Hom.: 1

Bravo AF: 0.00187

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000494 AC: 60

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

Pendred syndrome Uncertain:2 Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 16, 2019	- -
Benign, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Feb 25, 2019	The filtering allele frequency of the p.Ala357Thr variant in the SLC26A4 gene is 0.47% for African chromosomes by gnomAD (136/24968 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen Hearing Loss Expert Panel for autosomal recessive Pendred syndrome variants (BA1). The REVEL computational prediction analysis tool produces a score of 0.849, which is above the threshold necessary to apply PP3; however, this information is not predictive of pathogenicity on its own and is not considered in conflict with evidence that supports a benign interpretation. In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the Hearing Loss Expert Panel: BA1. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 19, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 02, 2016	p.Ala357Thr in exon 9 of SLC26A4: This variant is not expected to have clinical significance because it has been identified in 0.5% (53/10406) of African Americ an chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinsti tute.org; dbSNP rs145467740). In addition, this variant was found in a patient w ith two pathogenic variants which sufficiently explained their hearing loss. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 21, 2016	- -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SLC26A4-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.029	T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	1.8	L;L
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		0.99	D;D
Vest4		0.70
MVP		0.97
MPC		0.036
ClinPred		0.028	T
GERP RS		4.7
Varity_R		0.66
gMVP		0.94

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: rs145467740; hg19: chr7-107329565; COSMIC: COSV55918946; COSMIC: COSV55918946;