chr4-154744352-T-C

Position:

• chr4-154744352-T-C

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.26T>C​(p.Val9Ala) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V9V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.28

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 27 pathogenic changes around while only 5 benign (84%) in NM_004744.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10348362).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LRAT	NM_004744.5	c.26T>C	p.Val9Ala	missense_variant	2/3	ENST00000336356.4
LRAT	NM_001301645.2	c.26T>C	p.Val9Ala	missense_variant	2/3
LRAT	XM_047416405.1	c.26T>C	p.Val9Ala	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LRAT	ENST00000336356.4	c.26T>C	p.Val9Ala	missense_variant	2/3	1	NM_004744.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 9 of the LRAT protein (p.Val9Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with LRAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 955383). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.63
DEOGEN2	Benign	0.36	.;T;T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.73
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.49	T;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.10	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.71	.;N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.073
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.31	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.055
MutPred		0.29		Loss of glycosylation at P4 (P = 0.0835);Loss of glycosylation at P4 (P = 0.0835);Loss of glycosylation at P4 (P = 0.0835);
MVP		0.24
MPC		0.48
ClinPred		0.093	T
GERP RS		-0.44
Varity_R		0.049
gMVP		0.65

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: rs1732831177; hg19: chr4-155665504;