7-107690236-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3PP5_Strong

The NM_000441.2(SLC26A4):c.1262A>G(p.Gln421Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,550,504 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q421P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense, splice_region

Scores

Splicing: ADA: 0.9995

Clinical Significance

Uncertain significance reviewed by expert panel P:5U:3

Conservation

PhyloP100: 8.16

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM1

In a hotspot region, there are 6 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107690236-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 556159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

PP5

Variant 7-107690236-A-G is Pathogenic according to our data. Variant chr7-107690236-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 430229.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.1262A>G	p.Gln421Arg	missense_variant, splice_region_variant	10/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.1262A>G	p.Gln421Arg	missense_variant, splice_region_variant	10/21		NM_000441.2	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250686

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135452

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000122

AC:

AN:

1398330

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

699612

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000161

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000185

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:5Uncertain:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pendred syndrome

Pathogenic:2Uncertain:3

Uncertain significance, reviewed by expert panel	curation	ClinGen Hearing Loss Variant Curation Expert Panel	Jun 21, 2023	The c.1262A>G variant in SLC26A4 is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 421 (p.Gln421Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.003% (3/113084) in the European (non-Finnish) population, which is lower than the ClinGen Hearing Loss VCEP threshold (<0.007%) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.7, evidence that correlates with impact to SLC26A4 function (PP3). Another missense variant, c.1262A>C (p.Gln421Pro), at the same codon has been classified as likely pathogenic for autosomal recessive Pendred syndrome (PM5; PMID: 17718863, 23918157, 24224479, 28964290). The p.Gln421Arg variant has been reported in five individuals with hearing loss and inner ear abnormalities, which is highly specific for Pendred syndrome (PP4). Two individuals did not have a variant on the second allele identified (PMIDs: 23965030, 14679580). Two individuals were compound heterozygous for the CEVA haplotype, and one individual was compound heterozygous for a variant of uncertain significance, c.284G>A p.Gly95Glu. Phase for these individuals was unknown (0 PM3 points, PMID: 36833263). This variant was re-reviewed on 6.27.2023, and PM2 was downgraded to PM2_Supporting following the most recent specification criteria. Because no contradictory evidence was added, this variant was retained at likely pathogenic for autosomal recessive Pendrome syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Hearing Loss VCEP: PM5, PM2_Supporting, PP3, PP4. (VCEP specifications version 2; 06.21.2023). -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 21, 2022	Variant summary: SLC26A4 c.1262A>G (p.Gln421Arg) results in a conservative amino acid change located in the SLC26A/SulP transporter domain (IPR011547) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant weakens a 5' donor site. However, these predictions could not be confirmed experimentally where the variant was determined to exhibit wild-type splice form (Lee_2019). The variant allele was found at a frequency of 1.2e-05 in 250686 control chromosomes (gnomAD). c.1262A>G has been reported in the literature in a study of individuals with clinical diagnosis of dilated vestibular aqueduct or Mondini dysplasia (Prasad_2004). Other variants affecting the same amino acid residue (p.Q421L, p.Q421K, p.Q421P) have been cited in ClinVar and HGMD as pathogenic and disease-associated. These data indicate that the variant is likely to be associated with disease. Three ClinVar submitters including an expert panel (ClinGen Hearing Loss Variant Curation Expert Panel) (evaluation after 2014) cite the variant as likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostics Lab, Nemours Children's Health, Delaware	May 07, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 07, 2018	- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	The Shared Resource Centre "Genome", Research Centre for Medical Genetics	Nov 10, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 28, 2023	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 11, 2018

The Q421R variant in the SLC26A4 gene has been reported as a single heterozygous variant in an individual with hearing loss (Landa et al., 2013). It was also identified in another individual with a reported clinical diagnosis of Pendred syndrome; it was not specified whether this individual harbored a second SLC26A4 variant (Prasad et al., 2004). The Q421R variant was not observed at a significant frequency in large population cohorts (Lek et al., 2016). The Q421R variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Other missense variants at the same residue (Q421K, Q421P, Q421L) and missense variants nearby residues (T420I, V422I, V422D, G424D, I426N ) have been reported in the Human Gene Mutation Database in association with SLC26A4-related disorders (Stenson et al., 2014), supporting the functional importance of this residue and this region of the protein. Therefore, we classify this variant as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.48

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.74

D;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.95

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.0

M;M

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.8

D;.

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0010

D;.

Sift4G

Uncertain

0.0020

D;.

Polyphen

1.0

D;D

Vest4

0.97

MVP

0.98

MPC

0.076

ClinPred

0.99

GERP RS

5.1

Varity_R

0.94

gMVP

0.89

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.98

SpliceAI score (max)

0.43

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.43

Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over