chr7-107661669-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_000441.2(SLC26A4):c.28C>A(p.Pro10Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000111 in 1,570,026 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 0.00067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 1.56

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:

SLC26A4-AS1 (HGNC:22385): (SLC26A4 antisense RNA 1)

SLC26A4-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 167 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Trascript score misZ: -1.7621 (below the threshold of 3.09). GenCC associations: The gene is linked to athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062066913).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.28C>A	p.Pro10Thr	missense_variant	Exon 2 of 21	ENST00000644269.2	NP_000432.1	O43511-1
SLC26A4-AS1	NR_028137.1 link	n.130G>T		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.28C>A	p.Pro10Thr	missense_variant	Exon 2 of 21		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.000663

AC:

101

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00231

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.000160

AC:

AN:

181450

AF XY:

0.000101

show subpopulations

Gnomad AFR exome

AF:

0.00217

Gnomad AMR exome

AF:

0.000176

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000709

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000125

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000508

AC:

AN:

1417634

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

702236

show subpopulations

Gnomad4 AFR exome

AF:

0.00177

AC:

AN:

32794

Gnomad4 AMR exome

AF:

0.000178

AC:

AN:

39368

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

25504

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

37914

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

81424

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

41034

Gnomad4 NFE exome

AF:

0.00

AC:

AN:

1095062

Gnomad4 Remaining exome

AF:

0.0000848

AC:

AN:

58974

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000669

AC:

102

AN:

152392

Hom.:

Cov.:

AF XY:

0.000604

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.00233

AC:

0.00233162

AN:

0.00233162

Gnomad4 AMR

AF:

0.000196

AC:

0.000195925

AN:

0.000195925

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.00

AC:

AN:

Gnomad4 OTH

AF:

0.000945

AC:

0.00094518

AN:

0.00094518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000748

ESP6500AA

AF:

0.00121

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000937

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:1

Feb 06, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 30, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Pro10Thr variant in SLC26A4 has been reported in three individuals with enlarged vestibular aqueduct and in 1 individual with hearing loss (EVA; Madden 2007 PMID: 17309986, Greinwald 2013 PMID: 23401162, LMM data). One of these individuals also carried two additional variants in the SLC26A4 gene and it is unclear which of these variants, if any, are responsible for the EVA. It has also been identified in 0.2% (96/41480) of African chromosomes by gnomAD v. 3 (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 43550). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of this variant cannot be determined with certainty; however based upon the computational predictions and the presence of this variant in the general population, we would lean towards a more likely benign role. ACMG/AMP Criteria applied: BS1_P. -

Dec 01, 2022

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pendred syndrome

Uncertain:3

Jan 07, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Autosomal recessive nonsyndromic hearing loss 4

Uncertain:1

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC26A4-related disorder

Uncertain:1

May 10, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A4 c.28C>A variant is predicted to result in the amino acid substitution p.Pro10Thr. This variant was reported in an individual with enlarged vestibular aqueduct along with two other potentially pathogenic variants (described as P1028C>A, Madden. 2007. PubMed ID: 17309986) and has been reported as likely benign by an expert panel (Table S3, Azaiez. 2018. PubMed ID: 30245029). This variant is reported in 0.20% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107302114-C-A). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;T;T

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.34

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.73

.;T;T

M_CAP

Uncertain

0.20

MetaRNN

Benign

0.0062

T;T;T

MetaSVM

Benign

-0.45

MutationAssessor

Benign

0.0

N;N;.

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.0

N;.;N

REVEL

Uncertain

0.52

Sift

Benign

0.29

T;.;T

Sift4G

Benign

0.23

T;.;T

Polyphen

0.039

B;B;.

Vest4

0.18

MVP

0.82

MPC

0.012

ClinPred

0.013

GERP RS

3.2

Varity_R

0.056

gMVP

0.52

Mutation Taster

=74/26

polymorphism

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