7-107710183-G-T

Position:

• chr7-107710183-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1 PM2 PP5 BP4

The NM_000441.2(SLC26A4):​c.2219G>T​(p.Gly740Val) variant causes a missense change. The variant allele was found at a frequency of 0.000212 in 1,604,710 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G740S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:9
• Conservation: PhyloP100: 5.40

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 Uncertain_significance. Variant got 4 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
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-107710183-G-T is Pathogenic according to our data. 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=3}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.06387618). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.2219G>T	p.Gly740Val	missense_variant	19/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2219G>T	p.Gly740Val	missense_variant	19/21		NM_000441.2	ENSP00000494017.1
SLC26A4	ENST00000492030.2	n.405G>T		non_coding_transcript_exon_variant	4/6	5
SLC26A4	ENST00000644846.1	n.*121G>T		non_coding_transcript_exon_variant	8/10			ENSP00000494344.1
SLC26A4	ENST00000644846.1	n.*121G>T		3_prime_UTR_variant	8/10			ENSP00000494344.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000299 AC: 75 AN: 251252 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135786

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000209 AC: 303 AN: 1452584 Hom.: 1 Cov.: 27 AF XY: 0.000212 AC XY: 153 AN XY: 723258

Gnomad4 AFR exome AF: 0.000181

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000207

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74330

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000236 Hom.: 1

Bravo AF: 0.000208

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Pathogenic:1 Uncertain:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 13, 2024	Variant summary: SLC26A4 c.2219G>T (p.Gly740Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 251252 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (0.0003 vs 0.0035), allowing no conclusion about variant significance. c.2219G>T has been reported in the literature in individuals affected with Hearing loss (Albert_2006, Tang_2015, Baldyga_2023). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25788563, 25991456, 30240412, 30245029, 23804846, 18285825, 16570074, 23401162, 23965030, 20597900, 36833263).ClinVar contains an entry for this variant (Variation ID: 43545). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:1 Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 26, 2024	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2022	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 740 of the SLC26A4 protein (p.Gly740Val). This variant is present in population databases (rs111033310, gnomAD 0.1%). This missense change has been observed in individual(s) with deafness and/or clinical features of Pendred syndrome (PMID: 20597900, 23804846, 25788563, 25991456). ClinVar contains an entry for this variant (Variation ID: 43545). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SLC26A4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 13, 2024	Identified with an SLC26A4 variant of unknown significance in additional patients with hearing loss with or without enlarged vestibular aqueduct in published literature (PMID: 18285825, 16570074, 23965030); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 20597900, 30240412, 30245029, 23401162, 34426522, 25991456, 23965030, 16570074, 18285825, 35249537, 36147510, 25788563, 36833263, 23804846) -

Hearing impairment Pathogenic:1

Likely pathogenic, flagged submission

clinical testing

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Apr 12, 2021

PM2_Supporting, PM3_Moderate, PP4_Supporting -

Rare genetic deafness Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 02, 2023

Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Albert 2006 PMID: 16570074 1 proband (HL+EVA) with T307M (VUS) in cis, and Y530H (LP) in trans; 1 sib-pair (HL+EVA) with FS in trans, Landa 2013 PMID 23965030 2 probands with HL +EVA or goiter, 1 carries a splice variant (phase unknown), the second only het Makretskaya (2018) PMID: 30240412 Het in 1 pt with congenital hypothyroidism ACMG/AMP codes: PM3, PM2_Supporting (AJ high- however bottleneck pop). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.39	.;T
M_CAP	Uncertain	0.26	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Uncertain	0.021	D
MutationAssessor	Benign	0.0	N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.011	D;.
Polyphen		0.012	B;B
Vest4		0.35
MVP		0.96
MPC		0.011
ClinPred		0.042	T
GERP RS		5.5
Varity_R		0.16
gMVP		0.64

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: rs111033310; hg19: chr7-107350628;