rs397516417

Positions:

• chr7-107694479-AG-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000441.2(SLC26A4):​c.1341+1del variant causes a frameshift, splice region 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. 1/1 splice prediction tools predicting alterations to normal splicing. 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 NM_000441.2 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.05

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 7-107694479-AG-A is Pathogenic according to our data. Variant chr7-107694479-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 43505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC26A4	NM_000441.2	c.1341+1del		frameshift_variant, splice_region_variant	11/21	ENST00000644269.2	NP_000432.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC26A4	ENST00000644269.2	c.1341+1del		frameshift_variant, splice_region_variant	11/21		NM_000441.2	ENSP00000494017	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pendred syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	Severe to Profound SNHL -
Pathogenic, no assertion criteria provided	research	Hereditary Research Laboratory, Bethlehem University	Jun 04, 2016	severe to profound w/endolymphatic sac -

Autosomal recessive nonsyndromic hearing loss 4 Pathogenic:3

Pathogenic, criteria provided, single submitter	research	King Laboratory, University of Washington	Aug 01, 2020	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2023	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 11, 2021

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

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 20, 2014

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). -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs397516417; hg19: chr7-107334924;