rs5923

Variant names:

• chr16-67940050-G-A
• rs5923
• NM_000229.2:c.1177C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000229.2(LCAT):​c.1177C>T​(p.Leu393Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,613,446 control chromosomes in the GnomAD database, including 2,991 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.080 (733 hom., cov: 31)
  • Exomes 𝑓: 0.048 (2258 hom.)
• Consequence: LCAT NM_000229.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.231
• Publications: 43 publications found

Genes affected

LCAT (HGNC:6522): (lecithin-cholesterol acyltransferase) This gene encodes the extracellular cholesterol esterifying enzyme, lecithin-cholesterol acyltransferase. The esterification of cholesterol is required for cholesterol transport. Mutations in this gene have been found to cause fish-eye disease as well as LCAT deficiency. [provided by RefSeq, Jul 2008]

LCAT Gene-Disease associations (from GenCC):

• fish eye disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• LCAT deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Norum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-67940050-G-A is Benign according to our data. Variant chr16-67940050-G-A is described in ClinVar as Benign. ClinVar VariationId is 320196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.231 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCAT	NM_000229.2	c.1177C>T	p.Leu393Leu	synonymous_variant	Exon 6 of 6	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10	c.1177C>T	p.Leu393Leu	synonymous_variant	Exon 6 of 6	1	NM_000229.2	ENSP00000264005.5

Frequencies

GnomAD3 genomes AF: 0.0801 AC: 12185 AN: 152126 Hom.: 729 Cov.: 31

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0587

Gnomad ASJ AF: 0.0668

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0913

GnomAD2 exomes AF: 0.0484 AC: 12153 AN: 251128 AF XY: 0.0467

Gnomad AFR exome AF: 0.171

Gnomad AMR exome AF: 0.0356

Gnomad ASJ exome AF: 0.0688

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0287

Gnomad NFE exome AF: 0.0493

Gnomad OTH exome AF: 0.0519

GnomAD4 exome AF: 0.0481 AC: 70291 AN: 1461202 Hom.: 2258 Cov.: 31 AF XY: 0.0473 AC XY: 34412 AN XY: 726906

African (AFR) AF: 0.187 AC: 6247 AN: 33480

American (AMR) AF: 0.0373 AC: 1670 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0723 AC: 1889 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0288 AC: 2484 AN: 86258

European-Finnish (FIN) AF: 0.0303 AC: 1598 AN: 52746

Middle Eastern (MID) AF: 0.124 AC: 717 AN: 5768

European-Non Finnish (NFE) AF: 0.0470 AC: 52229 AN: 1112002

Other (OTH) AF: 0.0572 AC: 3455 AN: 60388

GnomAD4 genome AF: 0.0802 AC: 12203 AN: 152244 Hom.: 733 Cov.: 31 AF XY: 0.0771 AC XY: 5743 AN XY: 74440

African (AFR) AF: 0.175 AC: 7254 AN: 41536

American (AMR) AF: 0.0586 AC: 896 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0668 AC: 232 AN: 3472

East Asian (EAS) AF: 0.000967 AC: 5 AN: 5170

South Asian (SAS) AF: 0.0265 AC: 128 AN: 4822

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10614

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.0458 AC: 3112 AN: 68012

Other (OTH) AF: 0.0899 AC: 190 AN: 2114

Alfa AF: 0.0562 Hom.: 1498

Bravo AF: 0.0845

Asia WGS AF: 0.0250 AC: 86 AN: 3478

EpiCase AF: 0.0493

EpiControl AF: 0.0546

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Oct 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

LCAT deficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Fish-eye disease Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Mar 01, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Norum disease Benign:1

Aug 19, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.80
PhyloP100		-0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs5923; hg19: chr16-67973953;