dbSNP rs878853382: LCA5:p.Glu211AspfsTer13 (chr6-79513292-GTCTAGCT-G) – ACMG Classification: Pathogenic (18 pts)

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001122769.3(LCA5):c.633_639delAGCTAGA(p.Glu211AspfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000137 in 1,461,524 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: 0.0000014 ( 0 hom. )

Consequence

LCA5
NM_001122769.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 5.51

Variant links:

Genes affected

LCA5 (HGNC:31923): (lebercilin LCA5) This gene encodes a protein that is thought to be involved in centrosomal or ciliary functions. Mutations in this gene cause Leber congenital amaurosis type V. Alternatively spliced transcript variants are described. [provided by RefSeq, Oct 2009]

LCA5 links:

ENSG00000231533 (HGNC:):

ENSG00000231533 links:

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ACMG classification

Classification made for transcript

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 6-79513292-GTCTAGCT-G is Pathogenic according to our data. Variant chr6-79513292-GTCTAGCT-G is described in ClinVar as [Pathogenic]. Clinvar id is 236493.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-79513292-GTCTAGCT-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCA5	NM_001122769.3 link	c.633_639delAGCTAGA	p.Glu211AspfsTer13	frameshift_variant	Exon 3 of 8	ENST00000369846.9	NP_001116241.1	Q86VQ0A0A384MDJ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LCA5	ENST00000369846.9 link	c.633_639delAGCTAGA	p.Glu211AspfsTer13	frameshift_variant	Exon 3 of 8	1	NM_001122769.3	ENSP00000358861.4	Q86VQ0
LCA5	ENST00000392959.5 link	c.633_639delAGCTAGA	p.Glu211AspfsTer13	frameshift_variant	Exon 4 of 9	1		ENSP00000376686.1	Q86VQ0
LCA5	ENST00000467898.3 link	c.633_639delAGCTAGA	p.Glu211AspfsTer13	frameshift_variant	Exon 3 of 7	5		ENSP00000474463.1	S4R3K6
ENSG00000231533	ENST00000652956.1 link	n.470-13680_470-13674delTAGCTTC		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461524

Hom.:

AF XY:

0.00000275

AC XY:

AN XY:

727078

show subpopulations

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:4

Jan 01, 2015

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 24, 2018

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Apr 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over