4-154745783-T-G

Variant names:

• chr4-154745783-T-G
• rs201825
• NM_004744.5:c.540+917T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004744.5(LRAT):​c.540+917T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 151,966 control chromosomes in the GnomAD database, including 28,460 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.60 (28460 hom., cov: 32)
• Consequence: LRAT NM_004744.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.871
• Publications: 8 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: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.758 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRAT	NM_004744.5	MANE Select	c.540+917T>G		intron	N/A	NP_004735.2
	LRAT	NM_001301645.2		c.540+917T>G		intron	N/A	NP_001288574.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LRAT	ENST00000336356.4	TSL:1 MANE Select	c.540+917T>G		intron	N/A	ENSP00000337224.3
	LRAT	ENST00000507827.5	TSL:1	c.540+917T>G		intron	N/A	ENSP00000426761.1
	LRAT	ENST00000499392.1	TSL:1	n.472-2406T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.598 AC: 90789 AN: 151848 Hom.: 28411 Cov.: 32

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.444

Gnomad AMR AF: 0.662

Gnomad ASJ AF: 0.490

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.651

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.551

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.598 AC: 90898 AN: 151966 Hom.: 28460 Cov.: 32 AF XY: 0.610 AC XY: 45289 AN XY: 74272

African (AFR) AF: 0.765 AC: 31708 AN: 41448

American (AMR) AF: 0.662 AC: 10111 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 1702 AN: 3470

East Asian (EAS) AF: 0.710 AC: 3664 AN: 5158

South Asian (SAS) AF: 0.608 AC: 2914 AN: 4794

European-Finnish (FIN) AF: 0.651 AC: 6877 AN: 10556

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32184 AN: 67952

Other (OTH) AF: 0.556 AC: 1175 AN: 2114

Alfa AF: 0.495 Hom.: 12776

Bravo AF: 0.604

Asia WGS AF: 0.678 AC: 2360 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.54
DANN	Benign	0.57
PhyloP100		-0.87
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs201825; hg19: chr4-155666935;