rs104893848

Positions:

• chr4-154744851-T-A
• chr4-154744851-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_004744.5(LRAT):​c.525T>A​(p.Ser175Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 1.70

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain LRAT (size 127) in uniprot entity LRAT_HUMAN there are 11 pathogenic changes around while only 2 benign (85%) in NM_004744.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 4-154744851-T-A is Pathogenic according to our data. Variant chr4-154744851-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 5334.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-154744851-T-A is described in Lovd as [Likely_pathogenic]. Variant chr4-154744851-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRAT	NM_004744.5	c.525T>A	p.Ser175Arg	missense_variant	2/3	ENST00000336356.4	NP_004735.2
LRAT	NM_001301645.2	c.525T>A	p.Ser175Arg	missense_variant	2/3		NP_001288574.1
LRAT	XM_047416405.1	c.525T>A	p.Ser175Arg	missense_variant	2/3		XP_047272361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRAT	ENST00000336356.4	c.525T>A	p.Ser175Arg	missense_variant	2/3	1	NM_004744.5	ENSP00000337224	P1
LRAT	ENST00000507827.5	c.525T>A	p.Ser175Arg	missense_variant	2/3	1		ENSP00000426761	P1
LRAT	ENST00000510733.1	n.852T>A		non_coding_transcript_exon_variant	1/2	1
LRAT	ENST00000499392.1	n.472-3338T>A		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726936

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	Retina International	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 10, 2023	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 175 of the LRAT protein (p.Ser175Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with retinitis pigmentosa (PMID: 11381255, 22570351, 26656277). ClinVar contains an entry for this variant (Variation ID: 5334). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects LRAT function (PMID: 11381255). For these reasons, this variant has been classified as Pathogenic. -

RETINAL DYSTROPHY, EARLY-ONSET SEVERE, LRAT-RELATED Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D
Eigen	Benign	0.13
Eigen_PC	Benign	0.031
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	.;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	3.0	M;M
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.4	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.94		Gain of glycosylation at T172 (P = 0.0076);Gain of glycosylation at T172 (P = 0.0076);
MVP		0.88
MPC		1.3
ClinPred		0.99	D
GERP RS		2.3
Varity_R		0.76
gMVP		0.98

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: rs104893848; hg19: chr4-155666003;