rs111033407

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000441.2(SLC26A4):c.1342-2_1343dupAGTC(p.Leu450fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000134 in 1,608,410 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S448S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

SLC26A4
NM_000441.2 frameshift, splice_region

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 5.30

Publications

5 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-107694617-G-GCAGT is Pathogenic according to our data. Variant chr7-107694617-G-GCAGT is described in ClinVar as Pathogenic. ClinVar VariationId is 43506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC26A4	NM_000441.2 link	c.1342-2_1343dupAGTC	p.Leu450fs	frameshift_variant, splice_region_variant	Exon 12 of 21	ENST00000644269.2	NP_000432.1	O43511-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2 link	c.1342-4_1342-3insCAGT		splice_region_variant, intron_variant	Intron 11 of 20		NM_000441.2	ENSP00000494017.1		O43511-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152164

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000358

AC:

AN:

251046

AF XY:

0.0000295

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:

0.0000793

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000139

AC:

203

AN:

1456246

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

101

AN XY:

724902

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33342

American (AMR)

AF:

0.00

AC:

AN:

44684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39658

South Asian (SAS)

AF:

0.00

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000177

AC:

196

AN:

1106976

Other (OTH)

AF:

0.0000997

AC:

AN:

60174

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000854

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5204

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.000105

Hom.:

Bravo

AF:

0.0000642

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change falls in intron 11 of the SLC26A4 gene. It does not directly change the encoded amino acid sequence of the SLC26A4 protein. This variant is present in population databases (rs756270039, gnomAD 0.009%). This variant has been observed in individuals with deafness with enlargement of the vestibular aqueduct (PMID: 15689455, 19204907). This variant is also known as c.1342-2_1343dup (p.Leu450Glyfs*19) if splicing occurs at the native splice site. It is also referred to as c.1340_1343dup and 1343‚Äì1344insAGTC in the literature. ClinVar contains an entry for this variant (Variation ID: 43506). For these reasons, this variant has been classified as Pathogenic. -

Jun 19, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense-mediated mRNA decay in a gene for which loss-of-function is a known mechanism of disease; In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 19204907, 21704276, 31589614, 15689455) -

Pendred syndrome

Pathogenic:1

Nov 23, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Mar 18, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SLC26A4-related disorder

Pathogenic:1

Feb 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SLC26A4 c.1342-2_1343dupAGTC variant is predicted to result in a duplication affecting a canonical splice site. This variant has been reported along with a second SLC26A4 variant in individuals with an enlarged vestibular aqueduct (described as 1343-1344insAGTC in Pryor et al. 2005. PubMed ID: 15689455; described as c.1340_1343dup in Choi et al. 2009. PubMed ID: 19204907). This variant is reported in 0.0078% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-107335062-G-GCAGT). Taken together, this variant is interpreted as pathogenic. -

Rare genetic deafness

Pathogenic:1

Apr 27, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The 1342-2_1343dupAGTC variant in SLC26A4 has been reported as a compound hetero zygous variant in 3 individuals with enlarged vestibular aqueducts (EVA) and has been identified by our laboratory in 3 other individuals each of whom has a sec ond pathogenic SLC26A4 variant (Choi 2009, LMM unpublished data). This variant l eads to the duplication of a conserved splice site at the beginning of exon 12, which could either deleteriously affect splicing of the transcript or cause a fr ameshift if 4 additional bases are included in the exon. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). -

Pendred syndrome;C3538946:Autosomal recessive nonsyndromic hearing loss 4

Pathogenic:1

Apr 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.3

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

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