16-67942417-A-T

Variant names:

• chr16-67942417-A-T
• rs4986970
• NM_000229.2:c.694T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000229.2(LCAT):​c.694T>A​(p.Ser232Thr) variant causes a missense change. The variant allele was found at a frequency of 0.026 in 1,613,908 control chromosomes in the GnomAD database, including 650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S232A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 32)
  • Exomes 𝑓: 0.027 (619 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.82
• Publications: 51 publications found

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 Gene-Disease associations (from GenCC):

• fish eye disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• LCAT deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: Ambry Genetics
• Norum disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011052489).
• BP6: Variant 16-67942417-A-T is Benign according to our data. Variant chr16-67942417-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 884653.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0173 (2627/152236) while in subpopulation NFE AF = 0.0287 (1952/67990). AF 95% confidence interval is 0.0276. There are 31 homozygotes in GnomAd4. There are 1221 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000229.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	NM_000229.2	MANE Select	c.694T>A	p.Ser232Thr	missense	Exon 5 of 6	NP_000220.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.694T>A	p.Ser232Thr	missense	Exon 5 of 6	ENSP00000264005.5
	LCAT	ENST00000570980.1	TSL:2	c.478T>A	p.Ser160Thr	missense	Exon 4 of 5	ENSP00000464651.1
	LCAT	ENST00000576450.1	TSL:2	c.160T>A	p.Ser54Thr	missense	Exon 1 of 2	ENSP00000458141.1

Frequencies

GnomAD3 genomes AF: 0.0173 AC: 2628 AN: 152118 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00493

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00641

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0287

Gnomad OTH AF: 0.00718

GnomAD2 exomes AF: 0.0175 AC: 4389 AN: 251330 AF XY: 0.0175

Gnomad AFR exome AF: 0.00486

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0289

Gnomad OTH exome AF: 0.0143

GnomAD4 exome AF: 0.0269 AC: 39307 AN: 1461672 Hom.: 619 Cov.: 33 AF XY: 0.0261 AC XY: 18971 AN XY: 727152

African (AFR) AF: 0.00406 AC: 136 AN: 33480

American (AMR) AF: 0.00456 AC: 204 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26128

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00645 AC: 556 AN: 86258

European-Finnish (FIN) AF: 0.0270 AC: 1439 AN: 53248

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.0321 AC: 35743 AN: 1111984

Other (OTH) AF: 0.0199 AC: 1204 AN: 60390

GnomAD4 genome AF: 0.0173 AC: 2627 AN: 152236 Hom.: 31 Cov.: 32 AF XY: 0.0164 AC XY: 1221 AN XY: 74434

African (AFR) AF: 0.00491 AC: 204 AN: 41538

American (AMR) AF: 0.00804 AC: 123 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00642 AC: 31 AN: 4830

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0287 AC: 1952 AN: 67990

Other (OTH) AF: 0.00710 AC: 15 AN: 2112

Alfa AF: 0.0220 Hom.: 29

Bravo AF: 0.0155

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0283 AC: 109

ESP6500AA AF: 0.00660 AC: 29

ESP6500EA AF: 0.0306 AC: 263

ExAC AF: 0.0180 AC: 2188

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0235

EpiControl AF: 0.0228

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 23, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 22090275, 24503134)

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

LCAT deficiency Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

LCAT-related disorder Benign:1

Nov 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

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

May 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

May 22, 2019

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.53	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Benign	2.0	M
PhyloP100		4.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.57
Sift	Benign	0.19	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.98	D
Vest4		0.23
MPC		0.53
ClinPred		0.031	T
GERP RS		3.8
PromoterAI		-0.017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.63
gMVP		0.78
Mutation Taster		=86/14	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4986970; hg19: chr16-67976320; COSMIC: COSV107245592; COSMIC: COSV107245592;