16-67944067-G-A

Position:

• chr16-67944067-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000229.2(LCAT):​c.35C>T​(p.Thr12Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,548,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T12T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -0.0350

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]

SLC12A4 (HGNC:10913): (solute carrier family 12 member 4) This gene encodes a member of the SLC12A transporter family. The encoded protein mediates the coupled movement of potassium and chloride ions across the plasma membrane. This gene is expressed ubiquitously. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052141815).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00013 (182/1395936) while in subpopulation MID AF= 0.0039 (17/4360). AF 95% confidence interval is 0.00248. There are 0 homozygotes in gnomad4_exome. There are 101 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LCAT	NM_000229.2	c.35C>T	p.Thr12Met	missense_variant	1/6	ENST00000264005.10
SLC12A4	NM_005072.5	c.*773C>T		3_prime_UTR_variant	24/24	ENST00000316341.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LCAT	ENST00000264005.10	c.35C>T	p.Thr12Met	missense_variant	1/6	1	NM_000229.2	P1
SLC12A4	ENST00000316341.8	c.*773C>T		3_prime_UTR_variant	24/24	1	NM_005072.5	P1
LCAT	ENST00000575467.5	c.35C>T	p.Thr12Met	missense_variant, NMD_transcript_variant	1/6	5

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152136 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000158 AC: 24 AN: 152080 Hom.: 0 AF XY: 0.000161 AC XY: 13 AN XY: 80566

Gnomad AFR exome AF: 0.000121

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000529

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000875

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000130 AC: 182 AN: 1395936 Hom.: 0 Cov.: 32 AF XY: 0.000147 AC XY: 101 AN XY: 688442

Gnomad4 AFR exome AF: 0.000317

Gnomad4 AMR exome AF: 0.000224

Gnomad4 ASJ exome AF: 0.0000796

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000746

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000677

Gnomad4 OTH exome AF: 0.000225

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152254 Hom.: 1 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74432

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000743 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 12, 2022	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 12 of the LCAT protein (p.Thr12Met). This variant is present in population databases (rs560140762, gnomAD 0.05%). This missense change has been observed in individual(s) with low high-density lipoprotein cholesterol (PMID: 15994445, 21901787, 33816482). This variant is also known as T-13M. ClinVar contains an entry for this variant (Variation ID: 1348002). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Norum disease;C0342895:Fish-eye disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Dec 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	7.0
DANN	Benign	0.94
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.27
Sift	Benign	0.090	T
Sift4G	Benign	0.070	T
Polyphen		0.0010	B
Vest4		0.23
MutPred		0.28		Gain of disorder (P = 0.2854);
MVP		0.95
MPC		0.42
ClinPred		0.0089	T
GERP RS		2.3
Varity_R		0.020
gMVP		0.21

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: rs560140762; hg19: chr16-67977970;