rs397516417

Variant names:

• chr7-107694479-AG-A
• rs397516417
• ENST00000644269.2:c.1330delG

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PVS1 PM2 PP3_Moderate PP5_Very_Strong

The ENST00000644269.2(SLC26A4):​c.1330delG​(p.Leu445AsnfsTer8) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000686 in 1,457,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SLC26A4 ENST00000644269.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.05
• Publications: 4 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 20 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-107694479-AG-A is Pathogenic according to our data. Variant chr7-107694479-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 43505.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	c.1341+1delG		splice_donor_variant, intron_variant	Intron 11 of 20	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1330delG	p.Leu445AsnfsTer8	frameshift_variant	Exon 11 of 21		NM_000441.2	ENSP00000494017.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457680 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725416

African (AFR) AF: 0.00 AC: 0 AN: 33394

American (AMR) AF: 0.00 AC: 0 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.00 AC: 0 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108246

Other (OTH) AF: 0.00 AC: 0 AN: 60228

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:3

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Severe to Profound SNHL -

Jun 04, 2016

Hereditary Research Laboratory, Bethlehem University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

severe to profound w/endolymphatic sac -

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Feb 01, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2020

King Laboratory, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Analysis of patient-derived RNA indicates that SLC26A4 c.1341+1delG disrupts the splice donor of exon 11, with loss of 78bp in message and loss of aa 422-446, a complete transmembrane domain (Abu Rayyan 2020). The variant is compound heterozygous with SLC26A4 c.1149_1149+5 in 4 Palestinian children with severe to profound pre-lingual hearing loss and EVA. It is absent from 1300 Palestinian controls and from gnomAD v2.1.1. -

not provided Pathogenic:1

Dec 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 43505). This variant is also known as c.1341+1del, 1565delG, or 1565+1delG. This premature translational stop signal has been observed in individual(s) with SLC26A4-related conditions (PMID: 9398842, 19888295, 28964290). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys447Asnfs*8) in the SLC26A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC26A4 are known to be pathogenic (PMID: 16283880, 25394566, 26252218, 26445815). -

Rare genetic deafness Pathogenic:1

May 20, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1341+1delG variant in SLC26A4 has been reported in 5 probands with DFNB4/P endred syndrome, and segregated with hearing loss in 7 affected relatives in 2 f amilies (Everett 1997, Shahin 2010, Sheffield 1996, Tekin 2003, LMM unpublished data). Four out of 5 probands were homozygous or compound heterozygous. This var iant occurs in the invariant region (+/- 1/2) of the splice consensus sequence a nd is predicted to cause altered splicing leading to an abnormal or absent prote in. In summary, the c.1341+1delG variant meets our criteria to be classified as pathogenic (http://www.partners.org/personalizedmedicince/LMM). -

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

Jul 18, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.1
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 0
DS_DL_spliceai		0.96		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397516417; hg19: chr7-107334924;