4-154744404-T-A

Position:

• chr4-154744404-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_004744.5(LRAT):​c.78T>A​(p.Ser26Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 0.0650

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 193) in uniprot entity LRAT_HUMAN there are 15 pathogenic changes around while only 3 benign (83%) in NM_004744.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12880933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LRAT	NM_004744.5	c.78T>A	p.Ser26Arg	missense_variant	2/3	ENST00000336356.4	NP_004735.2
LRAT	NM_001301645.2	c.78T>A	p.Ser26Arg	missense_variant	2/3		NP_001288574.1
LRAT	XM_047416405.1	c.78T>A	p.Ser26Arg	missense_variant	2/3		XP_047272361.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LRAT	ENST00000336356.4	c.78T>A	p.Ser26Arg	missense_variant	2/3	1	NM_004744.5	ENSP00000337224	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast ductal adenocarcinoma Uncertain:1

Uncertain significance, no assertion criteria provided

research

Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Inc.

Jul 20, 2015

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.8
DANN	Benign	0.93
DEOGEN2	Benign	0.40	.;T;T
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.55	T;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	.;M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.10	T;T;T
Sift4G	Benign	0.21	T;T;T
Polyphen		0.80	.;P;P
Vest4		0.30
MutPred		0.42		Gain of methylation at S26 (P = 0.0353);Gain of methylation at S26 (P = 0.0353);Gain of methylation at S26 (P = 0.0353);
MVP		0.42
MPC		0.50
ClinPred		0.19	T
GERP RS		-1.7
Varity_R		0.045
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs869025235; hg19: chr4-155665556;