rs104893848

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_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

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 1.70

Variant links:

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]

LRAT links:

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ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
LRAT	NM_004744.5 link	c.525T>A	p.Ser175Arg	missense_variant	Exon 2 of 3	ENST00000336356.4	NP_004735.2	O95237
LRAT	NM_001301645.2 link	c.525T>A	p.Ser175Arg	missense_variant	Exon 2 of 3		NP_001288574.1	O95237
LRAT	XM_047416405.1 link	c.525T>A	p.Ser175Arg	missense_variant	Exon 2 of 3		XP_047272361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LRAT	ENST00000336356.4 link	c.525T>A	p.Ser175Arg	missense_variant	Exon 2 of 3	1	NM_004744.5	ENSP00000337224.3	O95237
LRAT	ENST00000507827.5 link	c.525T>A	p.Ser175Arg	missense_variant	Exon 2 of 3	1		ENSP00000426761.1	O95237
LRAT	ENST00000510733.1 link	n.852T>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
LRAT	ENST00000499392.1 link	n.472-3338T>A		intron_variant	Intron 5 of 5	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461278

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726936

show subpopulations

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.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Other:1

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Retina International

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

RETINAL DYSTROPHY, EARLY-ONSET SEVERE, LRAT-RELATED

Pathogenic:1

Jun 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Benign

0.13

Eigen_PC

Benign

0.031

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.85

.;D

M_CAP

Uncertain

0.25

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.12

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.56

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over