7-107701183-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000441.2(SLC26A4):c.1790T>C(p.Leu597Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00837 in 1,598,500 control chromosomes in the GnomAD database, including 125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene SLC26A4 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0062 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0086 ( 118 hom. )

Consequence

SLC26A4
NM_000441.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17

Conservation

PhyloP100: 6.17

Publications

47 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: Benign. The variant received -12 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 hearing loss, autosomal recessive, Pendred syndrome, autosomal recessive nonsyndromic hearing loss 4, thyroid hypoplasia, athyreosis.

BP4

Computational evidence support a benign effect (MetaRNN=0.008705229).

BP6

Variant 7-107701183-T-C is Benign according to our data. Variant chr7-107701183-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43525.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00623 (949/152304) while in subpopulation SAS AF = 0.0282 (136/4820). AF 95% confidence interval is 0.0244. There are 7 homozygotes in GnomAd4. There are 476 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

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.1790T>C	p.Leu597Ser	missense	Exon 16 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.1790T>C	p.Leu597Ser	missense	Exon 16 of 21	ENSP00000494017.1	O43511-1
SLC26A4	ENST00000888701.1		c.1790T>C	p.Leu597Ser	missense	Exon 15 of 20	ENSP00000558760.1
SLC26A4	ENST00000888700.1		c.1712T>C	p.Leu571Ser	missense	Exon 15 of 20	ENSP00000558759.1

Frequencies

GnomAD3 genomes

AF:

0.00624

AC:

949

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00687

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0282

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00813

Gnomad OTH

AF:

0.0100

GnomAD2 exomes

AF:

0.00833

AC:

2092

AN:

251102

AF XY:

0.00982

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00231

Gnomad ASJ exome

AF:

0.0206

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.000601

Gnomad NFE exome

AF:

0.00756

Gnomad OTH exome

AF:

0.00752

GnomAD4 exome

AF:

0.00860

AC:

12437

AN:

1446196

Hom.:

118

Cov.:

AF XY:

0.00942

AC XY:

6786

AN XY:

720586

show subpopulations

African (AFR)

AF:

0.00127

AC:

AN:

33116

American (AMR)

AF:

0.00255

AC:

114

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.0204

AC:

532

AN:

26040

East Asian (EAS)

AF:

0.00

AC:

AN:

39612

South Asian (SAS)

AF:

0.0294

AC:

2527

AN:

85892

European-Finnish (FIN)

AF:

0.000843

AC:

AN:

53374

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00782

AC:

8588

AN:

1097934

Other (OTH)

AF:

0.00826

AC:

494

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

528

1056

1584

2112

2640

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

342

684

1026

1368

1710

<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:

0.00623

AC:

949

AN:

152304

Hom.:

Cov.:

AF XY:

0.00639

AC XY:

476

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41564

American (AMR)

AF:

0.00686

AC:

105

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5190

South Asian (SAS)

AF:

0.0282

AC:

136

AN:

4820

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00813

AC:

553

AN:

68028

Other (OTH)

AF:

0.00994

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00791

Hom.:

Bravo

AF:

0.00601

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00960

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00823

AC:

999

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.00856

EpiControl

AF:

0.00794

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

not provided (5)

Pendred syndrome (4)

Autosomal recessive nonsyndromic hearing loss 4 (2)

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.67

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.80

MetaRNN

Benign

0.0087

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

2.0

PhyloP100

6.2

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-4.4

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0020

Sift4G

Benign

0.072

Polyphen

1.0

Vest4

0.75

MVP

0.99

MPC

0.074

ClinPred

0.013

GERP RS

5.7

Varity_R

0.66

gMVP

0.71

Mutation Taster

=84/16

polymorphism

(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