rs797045107

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000642402.1(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. R142R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SLC4A11 ENST00000642402.1 frameshift, synonymous
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 8.95
• Publications: 3 publications found

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]

SLC4A11 Gene-Disease associations (from GenCC):

• corneal dystrophy, Fuchs endothelial, 4

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• congenital hereditary endothelial dystrophy of cornea

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• corneal dystrophy-perceptive deafness syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, PanelApp Australia
• Fuchs' endothelial dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 208613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000642402.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A11	NM_001174089.2	MANE Select	c.425_433delGCTTCGCCAinsC	p.Arg142ProfsTer4	frameshift synonymous	Exon 5 of 20	NP_001167560.1
	SLC4A11	NM_001174090.2		c.554_562delGCTTCGCCAinsC	p.Arg185ProfsTer4	frameshift synonymous	Exon 5 of 20	NP_001167561.1
	SLC4A11	NM_032034.4		c.473_481delGCTTCGCCAinsC	p.Arg158ProfsTer4	frameshift synonymous	Exon 4 of 19	NP_114423.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SLC4A11	ENST00000642402.1	MANE Select	c.425_433delGCTTCGCCAinsC	p.Arg142ProfsTer4	frameshift synonymous	Exon 5 of 20	ENSP00000493503.1
	SLC4A11	ENST00000380056.7	TSL:1	c.473_481delGCTTCGCCAinsC	p.Arg158ProfsTer4	frameshift synonymous	Exon 4 of 19	ENSP00000369396.3
	SLC4A11	ENST00000380059.7	TSL:2	c.554_562delGCTTCGCCAinsC	p.Arg185ProfsTer4	frameshift synonymous	Exon 5 of 20	ENSP00000369399.3

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

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Congenital hereditary endothelial dystrophy of cornea (1)
1	-	-	Congenital hereditary endothelial dystrophy of cornea;C1857572:Corneal dystrophy-perceptive deafness syndrome;C2750450:Corneal dystrophy, Fuchs endothelial, 4 (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs797045107; hg19: chr20-3214819;