chr16-67943986-T-A

Variant names:

• chr16-67943986-T-A
• rs2058312868
• NM_000229.2:c.116A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000229.2(LCAT):​c.116A>T​(p.Lys39Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: LCAT NM_000229.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.978

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LCAT	NM_000229.2	c.116A>T	p.Lys39Met	missense_variant	Exon 1 of 6	ENST00000264005.10	NP_000220.1
SLC12A4	NM_005072.5	c.*854A>T		3_prime_UTR_variant	Exon 24 of 24	ENST00000316341.8	NP_005063.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LCAT	ENST00000264005.10	c.116A>T	p.Lys39Met	missense_variant	Exon 1 of 6	1	NM_000229.2	ENSP00000264005.5
SLC12A4	ENST00000316341	c.*854A>T		3_prime_UTR_variant	Exon 24 of 24	1	NM_005072.5	ENSP00000318557.3
LCAT	ENST00000575467.5	n.116A>T		non_coding_transcript_exon_variant	Exon 1 of 6	5		ENSP00000460653.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396324 Hom.: 0 Cov.: 32 AF XY: 0.00000145 AC XY: 1 AN XY: 688572

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jan 18, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.37	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.29
MutPred		0.30		Loss of ubiquitination at K39 (P = 0.0056);
MVP		0.98
MPC		1.1
ClinPred		0.84	D
GERP RS		5.1
Varity_R		0.12
gMVP		0.53

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: rs2058312868; hg19: chr16-67977889;