4-154744025-G-T

Variant summary

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

The NM_004744.5(LRAT):c.-199G>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 0.00296 in 435,592 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0070 (17 hom., cov: 31)
  • Exomes 𝑓: 0.00080 (3 hom.)
• Consequence: LRAT NM_004744.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.389

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 4-154744025-G-T is Benign according to our data. Variant chr4-154744025-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 902343.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.007 (1065/152196) while in subpopulation AFR AF= 0.0248 (1032/41530). AF 95% confidence interval is 0.0236. There are 17 homozygotes in gnomad4. There are 492 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRAT	NM_004744.5	c.-199G>T		5_prime_UTR_variant	1/3	ENST00000336356.4
LRAT	XM_047416405.1	c.-199G>T		5_prime_UTR_variant	1/3
LRAT	NM_001301645.2	c.-1-301G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRAT	ENST00000336356.4	c.-199G>T		5_prime_UTR_variant	1/3	1	NM_004744.5	P1

Frequencies

GnomAD3 genomes AF: 0.00699 AC: 1063 AN: 152078 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0249

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.000797 AC: 226 AN: 283396 Hom.: 3 Cov.: 0 AF XY: 0.000668 AC XY: 99 AN XY: 148284

Gnomad4 AFR exome AF: 0.0222

Gnomad4 AMR exome AF: 0.000659

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: 0.0000178

Gnomad4 OTH exome AF: 0.00127

GnomAD4 genome AF: 0.00700 AC: 1065 AN: 152196 Hom.: 17 Cov.: 31 AF XY: 0.00661 AC XY: 492 AN XY: 74404

Gnomad4 AFR AF: 0.0248

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000560 Hom.: 0

Bravo AF: 0.00761

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Retinitis pigmentosa Benign:1

Likely benign, 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	2.9
Dann	Benign	0.91

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: rs77224348; hg19: chr4-155665177;