Variant chr16-67940017-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_000229.2(LCAT):c.1210A>G(p.Met404Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000186 in 1,613,408 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

LCAT
NM_000229.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 5.02

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-67940017-T-C is Pathogenic according to our data. Variant chr16-67940017-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 626358.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCAT	NM_000229.2 linkuse as main transcript	c.1210A>G	p.Met404Val	missense_variant	6/6	ENST00000264005.10	NP_000220.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
LCAT	ENST00000264005.10 linkuse as main transcript	c.1210A>G	p.Met404Val	missense_variant	6/6	1	NM_000229.2	ENSP00000264005	P1
LCAT	ENST00000570369.5 linkuse as main transcript	c.215A>G	p.His72Arg	missense_variant	3/3	2		ENSP00000459014
LCAT	ENST00000573538.5 linkuse as main transcript	c.*531A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	3		ENSP00000463220

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461332

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726984

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

LCAT deficiency

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile

Apr 29, 2019

Methods: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. Results: LCAT sequencing identified rare p.V333M and p.M404V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363L variant. LCAT protein was detected in probandâ€™s plasma, but with undetectable enzyme activity compared to control relatives. HEK-239T transfected cells with vector expression plasmids containing either p.M404V or p.V333M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Conclusion: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404V and p.V333M in LCAT gene lead to suppression of LAT enzyme activity and cause clinical features of familial LCAT deficiency. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.63

Eigen

Benign

-0.032

Eigen_PC

Benign

0.081

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

M_CAP

Uncertain

0.16

MetaRNN

Uncertain

0.65

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

0.83

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-1.7

REVEL

Uncertain

0.54

Sift

Benign

0.046

Sift4G

Uncertain

0.0050

Polyphen

0.036

Vest4

0.66

MutPred

0.73

Gain of loop (P = 0.024);

MVP

0.92

MPC

0.49

ClinPred

0.80

GERP RS

3.4

Varity_R

0.42

gMVP

0.84

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over