4-154744851-T-C

Variant names:

• chr4-154744851-T-C
• rs104893848
• NM_004744.5:c.525T>C

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS1

The NM_004744.5(LRAT):​c.525T>C​(p.Ser175Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000806 in 1,613,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000079 (0 hom.)
• Consequence: LRAT NM_004744.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.70
• Publications: 13 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 4-154744851-T-C is Benign according to our data. Variant chr4-154744851-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1078570.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0000988 (15/151876) while in subpopulation NFE AF = 0.000191 (13/67950). AF 95% confidence interval is 0.000112. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.525T>C	p.Ser175Ser	synonymous	Exon 2 of 3	NP_004735.2
	LRAT	NM_001301645.2		c.525T>C	p.Ser175Ser	synonymous	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.525T>C	p.Ser175Ser	synonymous	Exon 2 of 3	ENSP00000337224.3	O95237
	LRAT	ENST00000507827.5	TSL:1	c.525T>C	p.Ser175Ser	synonymous	Exon 2 of 3	ENSP00000426761.1	O95237
	LRAT	ENST00000510733.1	TSL:1	n.852T>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000988 AC: 15 AN: 151876 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000564 AC: 14 AN: 248264 AF XY: 0.0000446

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000108

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461278 Hom.: 0 Cov.: 32 AF XY: 0.0000798 AC XY: 58 AN XY: 726936

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000980 AC: 109 AN: 1112004

Other (OTH) AF: 0.0000828 AC: 5 AN: 60392

GnomAD4 genome AF: 0.0000988 AC: 15 AN: 151876 Hom.: 0 Cov.: 31 AF XY: 0.0000809 AC XY: 6 AN XY: 74184

African (AFR) AF: 0.0000484 AC: 2 AN: 41350

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67950

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000907

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.51
PhyloP100		1.7

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: rs104893848; hg19: chr4-155666003;