chr16-67940050-G-A

Position:

• chr16-67940050-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000229.2(LCAT):​c.1177C>T​(p.Leu393=) 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 320196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67940050-G-A is described in Lovd as [Benign]. Variant chr16-67940050-G-A is described in Lovd as [Likely_benign].
• 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/exons	MANE	Protein	UniProt
LCAT	NM_000229.2	c.1177C>T	p.Leu393=	synonymous_variant	6/6	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10	c.1177C>T	p.Leu393=	synonymous_variant	6/6	1	NM_000229.2	ENSP00000264005	P1
LCAT	ENST00000570369.5	c.182C>T	p.Pro61Leu	missense_variant	3/3	2		ENSP00000459014
LCAT	ENST00000573538.5	c.*498C>T		3_prime_UTR_variant, NMD_transcript_variant	5/5	3		ENSP00000463220

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

GnomAD3 exomes AF: 0.0484 AC: 12153 AN: 251128 Hom.: 468 AF XY: 0.0467 AC XY: 6342 AN XY: 135830

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 SAS exome AF: 0.0297

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

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.0373

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0288

Gnomad4 FIN exome AF: 0.0303

Gnomad4 NFE exome AF: 0.0470

Gnomad4 OTH exome AF: 0.0572

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

Gnomad4 AFR AF: 0.175

Gnomad4 AMR AF: 0.0586

Gnomad4 ASJ AF: 0.0668

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0265

Gnomad4 FIN AF: 0.0266

Gnomad4 NFE AF: 0.0458

Gnomad4 OTH AF: 0.0899

Alfa AF: 0.0538 Hom.: 649

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

LCAT deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 01, 2019

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5923; hg19: chr16-67973953;