rs75368761

chr4-154744400-T-Achr4-154744400-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004744.5(LRAT):c.74T>A(p.Phe25Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00124 in 1,614,094 control chromosomes in the GnomAD database, including 29 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: 0.00065 (12 hom.)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: 1.92

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 -18 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 193) in uniprot entity LRAT_HUMAN there are 26 pathogenic changes around while only 5 benign (84%) in NM_004744.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.0054549873).
• BP6: Variant 4-154744400-T-A is Benign according to our data. Variant chr4-154744400-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 100574.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-154744400-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00697 (1061/152216) while in subpopulation AFR AF= 0.0247 (1028/41548). AF 95% confidence interval is 0.0235. There are 17 homozygotes in gnomad4. There are 491 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.74T>A	p.Phe25Tyr	missense_variant	2/3	ENST00000336356.4
LRAT	NM_001301645.2	c.74T>A	p.Phe25Tyr	missense_variant	2/3
LRAT	XM_047416405.1	c.74T>A	p.Phe25Tyr	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRAT	ENST00000336356.4	c.74T>A	p.Phe25Tyr	missense_variant	2/3	1	NM_004744.5	P1

Frequencies

GnomAD3 genomes AF: 0.00696 AC: 1059 AN: 152098 Hom.: 17 Cov.: 31

Gnomad AFR AF: 0.0248

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

GnomAD3 exomes AF: 0.00169 AC: 424 AN: 251436 Hom.: 8 AF XY: 0.000986 AC XY: 134 AN XY: 135900

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000646 AC: 944 AN: 1461878 Hom.: 12 Cov.: 31 AF XY: 0.000547 AC XY: 398 AN XY: 727240

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.000537

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: 0.00000809

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00697 AC: 1061 AN: 152216 Hom.: 17 Cov.: 31 AF XY: 0.00660 AC XY: 491 AN XY: 74440

Gnomad4 AFR AF: 0.0247

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: 0.00105 Hom.: 2

Bravo AF: 0.00766

ESP6500AA AF: 0.0284 AC: 125

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00229 AC: 278

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2 Other:1

not provided, no classification provided	literature only	NEI Ophthalmic Genomics Laboratory, National Institutes of Health	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 10, 2021

- -

Leber congenital amaurosis 14 Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Retinitis pigmentosa Benign:1

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.58	T;.;T
MetaRNN	Benign	0.0055	T;T;T
MetaSVM	Benign	-0.95	T
MutationTaster	Benign	0.99	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.20	T;D;D
Sift4G	Benign	0.20	T;T;T
Polyphen		0.96	.;D;D
Vest4		0.14
MVP		0.40
MPC		0.70
ClinPred		0.047	T
GERP RS		5.0
Varity_R		0.24
gMVP		0.64

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: rs75368761; hg19: chr4-155665552;