rs797045107

Variant names:

• chr20-3234173-TGGCGAAGC-G
• rs797045107
• NM_001174089.2:c.425_433delGCTTCGCCAinsC

Variant summary

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

The NM_001174089.2(SLC4A11):​c.425_433delGCTTCGCCAinsC​(p.Arg142ProfsTer4) variant causes a frameshift, synonymous change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. RFAR142P?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC4A11 NM_001174089.2 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.95

Genes affected

SLC4A11 (HGNC:16438): (solute carrier family 4 member 11) This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2010]

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 20-3234173-TGGCGAAGC-G is Pathogenic according to our data. Variant chr20-3234173-TGGCGAAGC-G is described in ClinVar as [Pathogenic]. Clinvar id is 208613.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
SLC4A11	NM_001174089.2	c.425_433delGCTTCGCCAinsC	p.Arg142ProfsTer4	frameshift_variant, synonymous_variant	Exon 5 of 20	ENST00000642402.1	NP_001167560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SLC4A11	ENST00000642402.1	c.425_433delGCTTCGCCAinsC	p.Arg142ProfsTer4	frameshift_variant, synonymous_variant	Exon 5 of 20		NM_001174089.2	ENSP00000493503.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital hereditary endothelial dystrophy of cornea;C1857572:Corneal dystrophy-perceptive deafness syndrome;C2750450:Corneal dystrophy, Fuchs endothelial, 4 Pathogenic:1

Jun 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

May 20, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18474783) -

Congenital hereditary endothelial dystrophy of cornea Pathogenic:1

Aug 29, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Arg185ProfsX4 variant in SLC4A11 has been reported as homozygous in 1 individual with corneal endothelial dystrophy 2 (Hemadevi 2008, described as Arg158ProfsX3). Data from large population studies is insufficient to assess the frequency of this variant. This frameshift variant is predicted to alter the protein’s amino acid sequence beginning at position 185 and lead to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. To date, several loss-of-function variants in SLC4A11 have been associated with corneal endothelial dystrophy 2. In summary, this variant meets our criteria to be classified as pathogenic for autosomal recessive corneal endothelial dystrophy (http://personalizedmedicine.partners.org/Laboratory-For-Molecular-Medicine/). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs797045107; hg19: chr20-3214819;