rs869320721

Variant names:

• chr20-3234173-TGGCGAAGC-T
• rs869320721
• NM_001174089.2:c.425_432delGCTTCGCC

Your query was ambiguous. Multiple possible variants found:

• chr20-3234173-TGGCGAAGC-T
• chr20-3234173-TGGCGAAGC-TGGCGAAGCGGCGAAGC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 16P and 4B. PVS1 PP5_Very_Strong BS2

The NM_001174089.2(SLC4A11):​c.425_432delGCTTCGCC​(p.Arg142GlnfsTer4) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,818 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000016 (1 hom.)
• Consequence: SLC4A11 NM_001174089.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 20-3234173-TGGCGAAGC-T is Pathogenic according to our data. Variant chr20-3234173-TGGCGAAGC-T is described in ClinVar as [Pathogenic]. Clinvar id is 1312.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-3234173-TGGCGAAGC-T is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAdExome4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SLC4A11	NM_001174089.2	c.425_432delGCTTCGCC	p.Arg142GlnfsTer4	frameshift_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_432delGCTTCGCC	p.Arg142GlnfsTer4	frameshift_variant	Exon 5 of 20		NM_001174089.2	ENSP00000493503.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 33

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461788 Hom.: 1 AF XY: 0.0000138 AC XY: 10 AN XY: 727190

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152030 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74256

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Corneal dystrophy-perceptive deafness syndrome Pathogenic:2

Jun 23, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Jul 23, 2020

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg158Glnfs*4) in the SLC4A11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC4A11 are known to be pathogenic (PMID: 17220209, 17679935). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of autosomal recessive congenital hereditary endothelial dystrophy (PMID: 17220209, 17679935). ClinVar contains an entry for this variant (Variation ID: 1312). For these reasons, this variant has been classified as Pathogenic. -

Congenital hereditary endothelial dystrophy of cornea Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift c.425_432del p.Arg142GlnfsTer4 variant in SLC4A11 gene has been previously reported in multiple individuals affected with corneal endothelial dystrophy Desir et al., 2007; Sultana et al., 2007. The p.Arg142GlnfsTer4 variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic multiple submissions. The variant p.Arg142GlnfsTer4 causes a frameshift change starting with codon Arginine 142, changes this amino acid to Glutamine residue, and creates a premature Stop codon at position 4 of the new reading frame, denoted p.Arg142GlnfsTer4. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

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: rs869320721; hg19: chr20-3214819;