chr7-107675060-T-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3PM1PP2PP3_ModeratePP5_Very_Strong

The NM_000441.2(SLC26A4):c.716T>A(p.Val239Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000954 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000060161: In vitro functional studies support an impact on protein function and have shown that protein trafficking is affected and iodide transport activity is reduced (Walsh 2005 PMID:16460646, Dossena 2011 PMID:22116360, Wassano 2020 PMID:19287372)." and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:29O:3

Conservation

PhyloP100: 4.50

Publications

51 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 4
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
Pendred syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
athyreosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
thyroid hypoplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

SLC26A4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 17 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000060161: In vitro functional studies support an impact on protein function and have shown that protein trafficking is affected and iodide transport activity is reduced (Walsh 2005 PMID: 16460646, Dossena 2011 PMID: 22116360, Wassano 2020 PMID: 19287372).; SCV001337950: Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh_2006, Dossena_2011).; SCV004048529: Experimental evidence reports the variant to lead to improper intracellular localization and retainment in the endoplasmic retuclum, and impaired protein function (Walsh T et.al.,2006).; SCV000947211: Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 16460646, 22116360).; SCV001766345: Published functional studies demonstrate that this variant reduces anion transport activity, affects protein localization and overall severely impairs normal protein function (Park et al., 2003; Dossena et al., 2011); SCV002058856: "Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 31599023)."; SCV002059883: SLC26A4 c.716T>A, p.V239D has been shown to decrease SLC26A4 ion transport activity (PMID: 22116360).; SCV002557167: Moderate functional evidence supporting abnormal protein function (Dossena, S. et al. (2011); Walsh, T. et al. (2006)). (P); SCV003926556: Experimental studies have shown that this missense change has a deleterious effect on protein function and localization (PMID: 16460646, 22116360); SCV004697373: Experimental studies have shown that this missense change affects SLC26A4 function Soh LM, et al., 2015; Shahzad M, et al., 2013; Dossena S, et al., 2011.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000441.2

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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.866

PP5

Variant 7-107675060-T-A is Pathogenic according to our data. Variant chr7-107675060-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 43566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000441.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC26A4	NM_000441.2	MANE Select	c.716T>A	p.Val239Asp	missense	Exon 6 of 21	NP_000432.1	O43511-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SLC26A4	ENST00000644269.2	MANE Select	c.716T>A	p.Val239Asp	missense	Exon 6 of 21	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000888701.1		c.716T>A	p.Val239Asp	missense	Exon 5 of 20	ENSP00000558760.1
SLC26A4	ENST00000888700.1		c.716T>A	p.Val239Asp	missense	Exon 6 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151978

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000203

AC:

AN:

251468

AF XY:

0.000302

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000101

AC:

147

AN:

1461808

Hom.:

Cov.:

AF XY:

0.000147

AC XY:

107

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00158

AC:

136

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111934

Other (OTH)

AF:

0.000116

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.0000460

AC:

AN:

152096

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41524

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00145

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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:

0.00

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.000239

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pendred syndrome (11)

Autosomal recessive nonsyndromic hearing loss 4 (8)

not provided (6)

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (3)

Deafness (1)

Hearing loss, autosomal recessive (1)

Rare genetic deafness (1)

Sensorineural hearing loss disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.84

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.52

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.92

MutationAssessor

Uncertain

2.4

PhyloP100

4.5

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.94

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.84

Vest4

0.96

MutPred

0.94

Loss of stability (P = 0.0337)

MVP

0.98

MPC

0.056

ClinPred

0.28

GERP RS

5.6

Varity_R

0.97

gMVP

0.98

Mutation Taster

=25/75

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over