16-67940188-G-C

Position:

• chr16-67940188-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The NM_000229.2(LCAT):​c.1039C>G​(p.Arg347Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000066 in 151,522 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R347C) has been classified as Pathogenic.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.169

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 4 ACMG points.

• PM1: In a strand (size 15) in uniprot entity LCAT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000229.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-67940188-G-A is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.13003194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LCAT	NM_000229.2	c.1039C>G	p.Arg347Gly	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.1039C>G	p.Arg347Gly	missense_variant	6/6	1	NM_000229.2	ENSP00000264005.5
LCAT	ENST00000570369.5	c.155-114C>G		intron_variant		2		ENSP00000459014.1
LCAT	ENST00000573538.5	n.*360C>G		non_coding_transcript_exon_variant	5/5	3		ENSP00000463220.1
LCAT	ENST00000573538.5	n.*360C>G		3_prime_UTR_variant	5/5	3		ENSP00000463220.1

Frequencies

GnomAD3 genomes AF: 0.00000660 AC: 1 AN: 151522 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000660 AC: 1 AN: 151522 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74000

Gnomad4 AFR AF: 0.0000243

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: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Uncertain	0.053	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	1.7
DANN	Benign	0.93
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.26	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.026	D
Sift4G	Benign	0.34	T
Polyphen		0.0020	B
Vest4		0.082
MutPred		0.56		Gain of glycosylation at T345 (P = 0.0971);
MVP		0.54
MPC		0.52
ClinPred		0.19	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.83

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: rs202017590; hg19: chr16-67974091;