rs17154353

chr7-107710182-G-Achr7-107710182-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000441.2(SLC26A4):c.2218G>A(p.Gly740Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00273 in 1,604,892 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G740V) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.014 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (43 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 5.59

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-107710183-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43545.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=8, Likely_pathogenic=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029495358).
• BP6: Variant 7-107710182-G-A is Benign according to our data. Variant chr7-107710182-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 43544.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107710182-G-A is described in Lovd as [Likely_benign]. Variant chr7-107710182-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0143 (2182/152248) while in subpopulation AFR AF= 0.0497 (2066/41528). AF 95% confidence interval is 0.048. There are 40 homozygotes in gnomad4. There are 1041 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2218G>A	p.Gly740Ser	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2218G>A	p.Gly740Ser	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000492030.2	n.404G>A		non_coding_transcript_exon_variant	4/6	5
SLC26A4	ENST00000644846.1	c.*120G>A		3_prime_UTR_variant, NMD_transcript_variant	8/10

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2182 AN: 152130 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.00369 AC: 928 AN: 251264 Hom.: 21 AF XY: 0.00281 AC XY: 382 AN XY: 135790

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00151 AC: 2194 AN: 1452644 Hom.: 43 Cov.: 27 AF XY: 0.00129 AC XY: 932 AN XY: 723258

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00217

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000175

Gnomad4 OTH exome AF: 0.00373

GnomAD4 genome AF: 0.0143 AC: 2182 AN: 152248 Hom.: 40 Cov.: 32 AF XY: 0.0140 AC XY: 1041 AN XY: 74456

Gnomad4 AFR AF: 0.0497

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00224 Hom.: 13

Bravo AF: 0.0165

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0502 AC: 221

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00437 AC: 530

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 14, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2010	Gly740Ser in exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance due a common occurrence in the general population (dbSNP - rs1715435 3). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 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. -

not provided Benign:5

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	SLC26A4: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 17, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Pendred syndrome Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 06, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 26, 2014	- -

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 06, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.068	T;T
Eigen	Benign	-0.15
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	0.70	N;.
REVEL	Uncertain	0.40
Sift	Benign	0.091	T;.
Sift4G	Benign	0.16	T;.
Polyphen		0.0	B;B
Vest4		0.33
MVP		0.98
MPC		0.011
ClinPred		0.023	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.60

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: rs17154353; hg19: chr7-107350627;