4-154744209-C-T

Variant summary

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

The NM_004744.5(LRAT):c.-15C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,090,240 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0054 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00061 (5 hom.)
• Consequence: LRAT NM_004744.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0700

Genes affected

LRAT (HGNC:6685): (lecithin retinol acyltransferase) The protein encoded by this gene localizes to the endoplasmic reticulum, where it catalyzes the esterification of all-trans-retinol into all-trans-retinyl ester. This reaction is an important step in vitamin A metabolism in the visual system. Mutations in this gene have been associated with early-onset severe retinal dystrophy and Leber congenital amaurosis 14. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00536 (816/152304) while in subpopulation AFR AF= 0.018 (750/41574). AF 95% confidence interval is 0.017. There are 4 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRAT	NM_004744.5	c.-15C>T		5_prime_UTR_variant	1/3	ENST00000336356.4
LRAT	XM_047416405.1	c.-15C>T		5_prime_UTR_variant	1/3
LRAT	NM_001301645.2	c.-1-117C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRAT	ENST00000336356.4	c.-15C>T		5_prime_UTR_variant	1/3	1	NM_004744.5	P1

Frequencies

GnomAD3 genomes AF: 0.00535 AC: 814 AN: 152186 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.000607 AC: 569 AN: 937936 Hom.: 5 Cov.: 13 AF XY: 0.000506 AC XY: 246 AN XY: 486072

Gnomad4 AFR exome AF: 0.0182

Gnomad4 AMR exome AF: 0.00140

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000109

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000764

Gnomad4 OTH exome AF: 0.00161

GnomAD4 genome AF: 0.00536 AC: 816 AN: 152304 Hom.: 4 Cov.: 31 AF XY: 0.00525 AC XY: 391 AN XY: 74466

Gnomad4 AFR AF: 0.0180

Gnomad4 AMR AF: 0.00346

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00444 Hom.: 2

Bravo AF: 0.00628

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Leber congenital amaurosis 14 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Retinitis pigmentosa Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	13
Dann	Benign	0.94

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: rs113018020; hg19: chr4-155665361;