rs4986970

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-67942417-A-C
• chr16-67942417-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000229.2(LCAT):​c.694T>G​(p.Ser232Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000031 in 1,613,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S232T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• LCAT deficiency

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42271537).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	NM_000229.2	MANE Select	c.694T>G	p.Ser232Ala	missense	Exon 5 of 6	NP_000220.1	P04180

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LCAT	ENST00000264005.10	TSL:1 MANE Select	c.694T>G	p.Ser232Ala	missense	Exon 5 of 6	ENSP00000264005.5	P04180
	LCAT	ENST00000570980.1	TSL:2	c.478T>G	p.Ser160Ala	missense	Exon 4 of 5	ENSP00000464651.1	J3QSE5
	LCAT	ENST00000576450.1	TSL:2	c.160T>G	p.Ser54Ala	missense	Exon 1 of 2	ENSP00000458141.1	I3L0J6

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251330 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461674 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 727154

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53248

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111986

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.000262 AC: 4 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 29

Bravo AF: 0.0000340

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	0.0096	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.55	D
Eigen	Benign	-0.021
Eigen_PC	Benign	0.13
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.42	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.6	L
PhyloP100		4.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.42
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.053	B
Vest4		0.25
MutPred		0.59		Gain of helix (P = 0.1736)
MVP		0.96
MPC		0.37
ClinPred		0.25	T
GERP RS		3.8
PromoterAI		0.0038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.50
gMVP		0.69

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;