rs142723249

chr7-107710154-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000441.2(SLC26A4):c.2190G>T(p.Gln730His) variant causes a missense change. The variant allele was found at a frequency of 0.000186 in 1,609,284 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00088 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: SLC26A4 NM_000441.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 3.78

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000441.2
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.009727389).
• BP6: Variant 7-107710154-G-T is Benign according to our data. Variant chr7-107710154-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 43543.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2	c.2190G>T	p.Gln730His	missense_variant	19/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2	c.2190G>T	p.Gln730His	missense_variant	19/21		NM_000441.2	P1
SLC26A4	ENST00000644846.1	c.*92G>T		3_prime_UTR_variant, NMD_transcript_variant	8/10
SLC26A4	ENST00000492030.2	n.377-1G>T		splice_acceptor_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000881 AC: 134 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000306 AC: 77 AN: 251294 Hom.: 1 AF XY: 0.000199 AC XY: 27 AN XY: 135804

Gnomad AFR exome AF: 0.00381

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000113 AC: 165 AN: 1457022 Hom.: 0 Cov.: 27 AF XY: 0.000110 AC XY: 80 AN XY: 725230

Gnomad4 AFR exome AF: 0.00351

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000542

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.000880 AC: 134 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000765 AC XY: 57 AN XY: 74466

Gnomad4 AFR AF: 0.00296

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000203 Hom.: 0

Bravo AF: 0.00110

ESP6500AA AF: 0.00250 AC: 11

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pendred syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 07, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 25, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 04, 2012	Gln730His in exon 19 of SLC26A4: This variant is not expected to have clinical s ignificance because it is has been identified in 0.3% (11/3738) of African Ameri can chromosomes from a broad population by the NHLBI Exome sequencing project (h ttp://evs.gs.washington.edu/EVS/; dbSNP rs142723249). -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2020	Observed heterozygous in unrelated patients with hearing loss in published literature (Landa et al., 2013; Chen et al., 2011); This variant is associated with the following publications: (PMID: 30245029, 21704276, 23965030) -

Autosomal recessive nonsyndromic hearing loss 4 Benign:1

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	0.18
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T;T
Eigen	Benign	0.0075
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.0097	T;T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.85	D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.2	N;.
REVEL	Uncertain	0.46
Sift	Benign	0.048	D;.
Sift4G	Benign	0.15	T;.
Polyphen		0.0050	B;B
Vest4		0.74
MutPred		0.42		Loss of stability (P = 0.0717);Loss of stability (P = 0.0717);
MVP		0.99
MPC		0.011
ClinPred		0.019	T
GERP RS		5.5
Varity_R		0.32
gMVP		0.67

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: rs142723249; hg19: chr7-107350599;