6-79485704-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001122769.3(LCA5):c.*1300G>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 0.0256 in 152,190 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (58 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: LCA5 NM_001122769.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0420

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-79485704-C-T is Benign according to our data. Variant chr6-79485704-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 358073.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0256 (3900/152190) while in subpopulation SAS AF= 0.0423 (204/4820). AF 95% confidence interval is 0.0376. There are 58 homozygotes in gnomad4. There are 1915 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 59 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCA5	NM_001122769.3	c.*1300G>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.*1300G>A		3_prime_UTR_variant	8/8	1	NM_001122769.3	P1
LCA5	ENST00000392959.5	c.*1300G>A		3_prime_UTR_variant	9/9	1		P1
	ENST00000652956.1	n.469+4264C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0257 AC: 3903 AN: 152072 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.00575

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0258

Gnomad ASJ AF: 0.0567

Gnomad EAS AF: 0.0394

Gnomad SAS AF: 0.0423

Gnomad FIN AF: 0.0224

Gnomad MID AF: 0.0833

Gnomad NFE AF: 0.0340

Gnomad OTH AF: 0.0411

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0256 AC: 3900 AN: 152190 Hom.: 58 Cov.: 32 AF XY: 0.0257 AC XY: 1915 AN XY: 74414

Gnomad4 AFR AF: 0.00573

Gnomad4 AMR AF: 0.0257

Gnomad4 ASJ AF: 0.0567

Gnomad4 EAS AF: 0.0395

Gnomad4 SAS AF: 0.0423

Gnomad4 FIN AF: 0.0224

Gnomad4 NFE AF: 0.0340

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0336 Hom.: 96

Bravo AF: 0.0247

Asia WGS AF: 0.0330 AC: 115 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 5 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	1.1
Dann	Benign	0.54

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: rs16890805; hg19: chr6-80195421; COSMIC: COSV63972802; COSMIC: COSV63972802;