16-67940004-T-C

Position:

• chr16-67940004-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000229.2(LCAT):​c.1223A>G​(p.Asn408Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.13

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a glycosylation_site N-linked (GlcNAc...) (complex) asparagine (size 0) in uniprot entity LCAT_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21918964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCAT	NM_000229.2	c.1223A>G	p.Asn408Ser	missense_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.1223A>G	p.Asn408Ser	missense_variant	6/6	1	NM_000229.2	ENSP00000264005	P1
LCAT	ENST00000570369.5	c.228A>G	p.Gln76=	synonymous_variant	3/3	2		ENSP00000459014
LCAT	ENST00000573538.5	c.*544A>G		3_prime_UTR_variant, NMD_transcript_variant	5/5	3		ENSP00000463220

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2023

The p.N408S variant (also known as c.1223A>G), located in coding exon 6 of the LCAT gene, results from an A to G substitution at nucleotide position 1223. The asparagine at codon 408 is replaced by serine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.025	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	22
DANN	Benign	0.90
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.37
Sift	Benign	0.70	T
Sift4G	Benign	0.43	T
Polyphen		0.065	B
Vest4		0.16
MutPred		0.59		Gain of sheet (P = 0.0061);
MVP		0.96
MPC		0.33
ClinPred		0.16	T
GERP RS		4.7
Varity_R		0.19
gMVP		0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-67973907;