7-107715429-C-T

Position:

• chr7-107715429-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000441.2(SLC26A4):​c.2326C>T​(p.Arg776Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00267 in 1,612,960 control chromosomes in the GnomAD database, including 7 homozygotes. 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 0.0018 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0028 (7 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:8
• Conservation: PhyloP100: 4.26

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 272) in uniprot entity S26A4_HUMAN there are 26 pathogenic changes around while only 8 benign (76%) in NM_000441.2
• BP4: Computational evidence support a benign effect (MetaRNN=0.027159065).
• BP6: Variant 7-107715429-C-T is Benign according to our data. Variant chr7-107715429-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43547.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=2}. Variant chr7-107715429-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2326C>T	p.Arg776Cys	missense_variant	21/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2326C>T	p.Arg776Cys	missense_variant	21/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.512C>T		non_coding_transcript_exon_variant	6/6	5
SLC26A4	ENST00000644846.1	n.*228C>T		non_coding_transcript_exon_variant	10/10			ENSP00000494344.1
SLC26A4	ENST00000644846.1	n.*228C>T		3_prime_UTR_variant	10/10			ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.00178 AC: 270 AN: 152090 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00293

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00181 AC: 455 AN: 251434 Hom.: 0 AF XY: 0.00191 AC XY: 260 AN XY: 135902

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000457

Gnomad FIN exome AF: 0.00268

Gnomad NFE exome AF: 0.00287

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00276 AC: 4030 AN: 1460752 Hom.: 7 Cov.: 29 AF XY: 0.00265 AC XY: 1926 AN XY: 726758

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000693

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000301

Gnomad4 FIN exome AF: 0.00307

Gnomad4 NFE exome AF: 0.00324

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152208 Hom.: 0 Cov.: 31 AF XY: 0.00180 AC XY: 134 AN XY: 74432

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00283

Gnomad4 NFE AF: 0.00293

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00176

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00200 AC: 243

EpiCase AF: 0.00284

EpiControl AF: 0.00284

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	SLC26A4: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 03, 2020	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Pendred syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 02, 2015	p.Arg776Cys in exon 21 of SLC26A4: This variant has been reported in six proband s with non-syndromic hearing loss with/without EVA (Pryor 2005, Choi 2009, Hutch in 2005, Pourova 2010). However, haplotype analysis in one of the reported famil ies showed inconsistent segregation of the SLC26A4 gene in an affected sibling, suggesting that SLC26A4 mutations were not the primary cause of hearing loss in that family. This variant has been identified in 0.5% (33/6614) of Finnish chro mosomes and in 0.3% (192/66740) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs111033255). In addit ion, this variant has now been identified in our laboratory in 2 patients with a nother genetic cause of their hearing loss. In addition, two independent functio nal studies show that the variant allele had a similar function to wildtype (Pfa rr 2006, Choi 2009). In summary, the current data suggest that this variant is l ikely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 4 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T;T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.027	T;T
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N;.
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;.
Polyphen		1.0	D;D
Vest4		0.48
MVP		0.99
MPC		0.041
ClinPred		0.019	T
GERP RS		5.8
Varity_R		0.17
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs111033255; hg19: chr7-107355874; COSMIC: COSV55916018;