rs878853382

Positions:

• chr6-79513292-GTCTAGCT-G

Variant summary

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

The NM_001122769.3(LCA5):​c.633_639delAGCTAGA​(p.Glu211fs) 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.51

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]

ENSG00000231533 (HGNC:):

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 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/exons	MANE	Protein	UniProt
LCA5	NM_001122769.3	c.633_639delAGCTAGA	p.Glu211fs	frameshift_variant	3/8	ENST00000369846.9	NP_001116241.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCA5	ENST00000369846.9	c.633_639delAGCTAGA	p.Glu211fs	frameshift_variant	3/8	1	NM_001122769.3	ENSP00000358861.4
LCA5	ENST00000392959.5	c.633_639delAGCTAGA	p.Glu211fs	frameshift_variant	4/9	1		ENSP00000376686.1
LCA5	ENST00000467898.3	c.633_639delAGCTAGA	p.Glu211fs	frameshift_variant	3/7	5		ENSP00000474463.1
ENSG00000231533	ENST00000652956.1	n.470-13680_470-13674delTAGCTTC		intron_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461524 Hom.: 0 AF XY: 0.00000275 AC XY: 2 AN XY: 727078

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Retinal dystrophy Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2023	- -
Pathogenic, no assertion criteria provided	research	NIHR Bioresource Rare Diseases, University of Cambridge	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Oct 24, 2018	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Centre for Genomic Medicine, Manchester, Central Manchester University Hospitals	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2018

- -

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: rs878853382; hg19: chr6-80223009;