7-107704355-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM1PP2BP4

The NM_000441.2(SLC26A4):c.2059G>T(p.Asp687Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000657 in 1,399,428 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 1 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:8

Conservation

PhyloP100: 5.39

Publications

7 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen
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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 autosomal recessive nonsyndromic hearing loss 4, Pendred syndrome, athyreosis, thyroid hypoplasia, hearing loss, autosomal recessive.

BP4

Computational evidence support a benign effect (MetaRNN=0.35744894).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.2059G>T	p.Asp687Tyr	missense_variant	Exon 18 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SLC26A4	ENST00000644269.2 link	c.2059G>T	p.Asp687Tyr	missense_variant	Exon 18 of 21		NM_000441.2	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000492030.2 link	n.346G>T		non_coding_transcript_exon_variant	Exon 3 of 6	5
SLC26A4	ENST00000644846.1 link	n.744+2298G>T		intron_variant	Intron 7 of 9			ENSP00000494344.1	A0A2R8Y4W7

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

GnomAD2 exomes

AF:

0.0000746

AC:

AN:

227856

AF XY:

0.0000897

show subpopulations

Gnomad AFR exome

AF:

0.00103

Gnomad AMR exome

AF:

0.0000598

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:

0.0000289

AC:

AN:

1247170

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

629090

show subpopulations

African (AFR)

AF:

0.00112

AC:

AN:

29550

American (AMR)

AF:

0.0000459

AC:

AN:

43570

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24306

East Asian (EAS)

AF:

0.00

AC:

AN:

38642

South Asian (SAS)

AF:

0.00

AC:

AN:

80434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51974

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5354

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

920492

Other (OTH)

AF:

0.0000189

AC:

AN:

52848

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.437

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:

0.000368

AC:

AN:

152258

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41554

American (AMR)

AF:

0.0000653

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.000171

Hom.:

Bravo

AF:

0.000408

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pendred syndrome

Uncertain:3

Feb 19, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 28, 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Jul 31, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SLC26A4 c.2059G>T (p.Asp687Tyr) results in a non-conservative amino acid change located in the STAS domain (IPR002645) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 227856 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in SLC26A4 causing Pendred Syndrome (7.5e-05 vs 0.0035), allowing no conclusion about variant significance. c.2059G>T has been reported in the literature in at-least one individual affected with non-syndromic hearing loss, without strong evidence for causality (Perry_2022). These report(s) do not provide unequivocal conclusions about association of the variant with Pendred Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 60% of normal activity in HEK 293 cells (Dossena_2011). The following publications have been ascertained in the context of this evaluation (PMID: 22116359, 36515421). ClinVar contains an entry for this variant (Variation ID: 43535). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Oct 30, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. The Asp687Tyr v ariant in SLC26A4 has not been previously identified by our laboratory. One stud y has shown that the Asp687Tyr variant impacts protein function (Dossena 2011). Computational analyses (biochemical amino acid properties, conservation, AlignGV GD, PolyPhen2, and SIFT) also suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Th is variant has been identified in 0.1% (6/4376) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.was hington.edu/EVS/; dbSNP rs35548413); however, this frequency is not high enough to rule out a pathogenic role. In summary, the clinical significance of this var iant cannot be determined with certainty; however, based upon the functional dat a, we would lean towards a more likely pathogenic role. -

not provided

Uncertain:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 01, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect on the ion transport activity of pendrin(PMID: 22116359); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22116355, 22116359, 28941661, 36515421) -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.057

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.80

D;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

.;D

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.36

T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

5.4

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-5.8

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.012

D;.

Sift4G

Uncertain

0.0040

D;.

Polyphen

0.94

P;P

Vest4

0.83

MVP

0.98

MPC

0.071

ClinPred

0.41

GERP RS

4.5

Varity_R

0.72

gMVP

0.81

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over