rs111033304

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM1BP4_StrongBP6_Very_StrongBS2

The NM_000441.2(SLC26A4):c.898A>C(p.Ile300Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,613,866 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 4 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 8.46

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 Benign. Variant got -14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000441.2

BP4

Computational evidence support a benign effect (MetaRNN=0.014808357).

BP6

Variant 7-107683334-A-C is Benign according to our data. Variant chr7-107683334-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 43570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-107683334-A-C is described in Lovd as [Likely_benign]. Variant chr7-107683334-A-C is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC26A4	NM_000441.2 linkuse as main transcript	c.898A>C	p.Ile300Leu	missense_variant	7/21	ENST00000644269.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC26A4	ENST00000644269.2 linkuse as main transcript	c.898A>C	p.Ile300Leu	missense_variant	7/21		NM_000441.2	P1	O43511-1

Frequencies

GnomAD3 genomes

AF:

0.00417

AC:

635

AN:

152212

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

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:

0.00239

GnomAD3 exomes

AF:

0.00100

AC:

252

AN:

251282

Hom.:

AF XY:

0.000729

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.000492

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:

0.0000264

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000409

AC:

598

AN:

1461536

Hom.:

Cov.:

AF XY:

0.000325

AC XY:

236

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.0155

Gnomad4 AMR exome

AF:

0.000537

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:

0.00000450

Gnomad4 OTH exome

AF:

0.000762

GnomAD4 genome

AF:

0.00418

AC:

636

AN:

152330

Hom.:

Cov.:

AF XY:

0.00426

AC XY:

317

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.0145

Gnomad4 AMR

AF:

0.00157

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:

0.00237

Alfa

AF:

0.000528

Hom.:

Bravo

AF:

0.00475

ESP6500AA

AF:

0.0104

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00123

AC:

149

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SLC26A4: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 25394566, 23617710, 21045265, 23280318, 30245029) -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 21, 2011	Ile300Leu in exon 7 of SLC26A4: This variant is predicted to be benign because i t has been identified in 1.3% (140/10384) of African chromosomes including 3 hom ozygotes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs111033304). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 30, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Pendred syndrome

Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 01, 2020	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 26, 2014	- -

SLC26A4-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.63

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

.;D

MetaRNN

Benign

0.015

T;T

MetaSVM

Uncertain

0.37

MutationAssessor

Benign

1.6

L;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-1.9

N;.

REVEL

Pathogenic

0.69

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.020

D;.

Polyphen

0.97

D;D

Vest4

0.76

MVP

0.96

MPC

0.076

ClinPred

0.026

GERP RS

5.3

Varity_R

0.57

gMVP

0.87

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

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