rs143708308

chr7-107710103-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000441.2(SLC26A4):c.2139T>G(p.Ile713Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000521 in 1,611,228 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (4 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0640

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 -14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000441.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.0098332465).
• BP6: Variant 7-107710103-T-G is Benign according to our data. Variant chr7-107710103-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 43540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107710103-T-G is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2139T>G	p.Ile713Met	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2139T>G	p.Ile713Met	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000644846.1	c.*41T>G		3_prime_UTR_variant, NMD_transcript_variant	8/10
SLC26A4	ENST00000492030.2	n.377-52T>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152204 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00871

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000677 AC: 170 AN: 251288 Hom.: 2 AF XY: 0.000412 AC XY: 56 AN XY: 135810

Gnomad AFR exome AF: 0.00947

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000319 AC: 465 AN: 1458906 Hom.: 4 Cov.: 29 AF XY: 0.000249 AC XY: 181 AN XY: 726038

Gnomad4 AFR exome AF: 0.0113

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.000929

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152322 Hom.: 2 Cov.: 32 AF XY: 0.00227 AC XY: 169 AN XY: 74486

Gnomad4 AFR AF: 0.00868

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000465 Hom.: 0

Bravo AF: 0.00316

ESP6500AA AF: 0.00840 AC: 37

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000782 AC: 95

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2022	Variant summary: SLC26A4 c.2139T>G (p.Ile713Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00068 in 251288 control chromosomes, predominantly at a frequency of 0.0095 within the African or African-American subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC26A4 causing Pendred Syndrome phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Although reported in the literature as a benign variation supported by the Deafness Variation Database (example, Azaiez_2018), to our knowledge, no occurrence of c.2139T>G in individuals affected with Pendred Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ile713Met in Exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (27/3736) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http ://evs.gs.washington.edu/EVS; dbSNP rs143708308). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2016	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 07, 2020	This variant is associated with the following publications: (PMID: 30245029, 25262649, 19509082) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	SLC26A4: BS1, BS2 -

Pendred syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Dec 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 16, 2020	- -

SLC26A4-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2020

This variant is classified as 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	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;D
Eigen	Benign	0.071
Eigen_PC	Benign	-0.031
FATHMM_MKL	Benign	0.64	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.0098	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.0	M;M
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.0	N;.
REVEL	Uncertain	0.50
Sift	Uncertain	0.012	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.84	P;P
Vest4		0.32
MVP		0.96
MPC		0.012
ClinPred		0.042	T
GERP RS		-1.7
Varity_R		0.29
gMVP		0.55

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: rs143708308; hg19: chr7-107350548;