6-79485252-C-T

Position:

• chr6-79485252-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001122769.3(LCA5):​c.*1752G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00832 in 152,306 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (0 hom.)
• Consequence: LCA5 NM_001122769.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.219

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00832 (1263/151874) while in subpopulation NFE AF= 0.0137 (927/67898). AF 95% confidence interval is 0.0129. There are 11 homozygotes in gnomad4. There are 572 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCA5	NM_001122769.3	c.*1752G>A		3_prime_UTR_variant	8/8	ENST00000369846.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCA5	ENST00000369846.9	c.*1752G>A		3_prime_UTR_variant	8/8	1	NM_001122769.3	P1
LCA5	ENST00000392959.5	c.*1752G>A		3_prime_UTR_variant	9/9	1		P1
	ENST00000652956.1	n.469+3812C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.00832 AC: 1263 AN: 151756 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00242

Gnomad AMI AF: 0.0384

Gnomad AMR AF: 0.00532

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00733

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00766

GnomAD4 exome AF: 0.00926 AC: 4 AN: 432 Hom.: 0 Cov.: 0 AF XY: 0.0115 AC XY: 3 AN XY: 260

Gnomad4 FIN exome AF: 0.00939

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00832 AC: 1263 AN: 151874 Hom.: 11 Cov.: 32 AF XY: 0.00771 AC XY: 572 AN XY: 74214

Gnomad4 AFR AF: 0.00241

Gnomad4 AMR AF: 0.00531

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00733

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00369 Hom.: 2

Bravo AF: 0.00771

Asia WGS AF: 0.00468 AC: 16 AN: 3434

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	4.8
DANN	Benign	0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1394281; hg19: chr6-80194969;