7-107674970-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PS3PM5PP2PP3_StrongPP5_Very_Strong

The NM_000441.2(SLC26A4):c.626G>T(p.Gly209Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,613,932 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329518: Published functional studies demonstrate a damaging effect on iodide transport (Taylor et al., 2002)" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G209E) has been classified as Likely pathogenic. The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00076 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:25

Conservation

PhyloP100: 9.43

Publications

35 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

Specifications for SLC26A4 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000329518: Published functional studies demonstrate a damaging effect on iodide transport (Taylor et al., 2002);; SCV000960084: Experimental studies have shown that this missense change affects SLC26A4 function (PMID: 11932316).; SCV004700675: PS3:Supporting; SCV000915191: "In HeLa cells, the p.Gly209Val variant showed normal cellular localization, but reduced iodide efflux compared to wildtype (Taylor et al. 2002)."

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-107674970-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 2735064.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.967

PP5

Variant 7-107674970-G-T is Pathogenic according to our data. Variant chr7-107674970-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 4821.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.626G>T	p.Gly209Val	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.626G>T	p.Gly209Val	missense	Exon 6 of 21	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000888701.1		c.626G>T	p.Gly209Val	missense	Exon 5 of 20	ENSP00000558760.1
SLC26A4	ENST00000888700.1		c.626G>T	p.Gly209Val	missense	Exon 6 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes

AF:

0.000362

AC:

AN:

152052

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000302

AC:

AN:

251470

AF XY:

0.000272

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000607

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000760

AC:

1111

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000727

AC XY:

529

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000112

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000941

AC:

1046

AN:

1111998

Other (OTH)

AF:

0.000844

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

110

165

220

275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000362

AC:

AN:

152052

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74288

show subpopulations

African (AFR)

AF:

0.0000966

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.0000944

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

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:

0.000500

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000247

AC:

EpiCase

AF:

0.000709

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Autosomal recessive nonsyndromic hearing loss 4 (6)

Pendred syndrome (6)

not provided (5)

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (2)

SLC26A4-related disorder (2)

Ear malformation (1)

Hearing impairment (1)

Monogenic hearing loss (1)

Rare genetic deafness (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.98

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.6

PhyloP100

9.4

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-8.9

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

1.0

MVP

0.99

MPC

0.075

ClinPred

0.94

GERP RS

5.6

Varity_R

0.99

gMVP

0.95

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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