chr4-154744381-A-G

Variant names:

• chr4-154744381-A-G
• NM_004744.5:c.55A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004744.5(LRAT):​c.55A>G​(p.Ile19Val) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LRAT NM_004744.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.439
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Leber congenital amaurosis 14

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• Leber congenital amaurosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• retinitis pigmentosa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe early-childhood-onset retinal dystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.076893955).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004744.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRAT	NM_004744.5	MANE Select	c.55A>G	p.Ile19Val	missense	Exon 2 of 3	NP_004735.2
	LRAT	NM_001301645.2		c.55A>G	p.Ile19Val	missense	Exon 2 of 3	NP_001288574.1	O95237

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRAT	ENST00000336356.4	TSL:1 MANE Select	c.55A>G	p.Ile19Val	missense	Exon 2 of 3	ENSP00000337224.3	O95237
	LRAT	ENST00000507827.5	TSL:1	c.55A>G	p.Ile19Val	missense	Exon 2 of 3	ENSP00000426761.1	O95237
	LRAT	ENST00000510733.1	TSL:1	n.382A>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.8
DANN	Benign	0.65
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.077	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.44
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.051
Sift	Benign	0.22	T
Sift4G	Benign	0.24	T
Polyphen		0.0	B
Vest4		0.049
MutPred		0.22		Loss of catalytic residue at L24 (P = 0.0443)
MVP		0.25
MPC		0.33
ClinPred		0.048	T
GERP RS		-4.4
PromoterAI		0.042	Neutral
Varity_R		0.025
gMVP		0.53
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

hg19: chr4-155665533;