NM_000229.2:c.1291A>G

Variant names:

• chr16-67939936-T-C
• rs1471466689
• NM_000229.2:c.1291A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000229.2(LCAT):​c.1291A>G​(p.Thr431Ala) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.68
• Publications: 0 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052642196).
• BP6: Variant 16-67939936-T-C is Benign according to our data. Variant chr16-67939936-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1769101.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1291A>G	p.Thr431Ala	missense	Exon 6 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.1291A>G	p.Thr431Ala	missense	Exon 6 of 6	ENSP00000264005.5	P04180
	LCAT	ENST00000570369.5	TSL:2	c.293A>G	p.Asp98Gly	missense	Exon 3 of 3	ENSP00000459014.1	I3L1Q6
	LCAT	ENST00000573538.5	TSL:3	n.*612A>G		non_coding_transcript_exon	Exon 5 of 5	ENSP00000463220.1	J3QKT0

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.040
DANN	Benign	0.40
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.25	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.053	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.14	N
PhyloP100		-1.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.24
Sift	Benign	0.49	T
Sift4G	Benign	0.81	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.18		Loss of glycosylation at T431 (P = 1e-04)
MVP		0.66
MPC		0.39
ClinPred		0.025	T
GERP RS		-6.3
Varity_R		0.082
gMVP		0.44

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: rs1471466689; hg19: chr16-67973839;