20-45899645-A-G

Variant names:

• chr20-45899645-A-G
• rs760077699
• NM_006227.4:c.1259T>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006227.4(PLTP):​c.1259T>C​(p.Ile420Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: PLTP NM_006227.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.63

Genes affected

PLTP (HGNC:9093): (phospholipid transfer protein) The protein encoded by this gene is one of at least two lipid transfer proteins found in human plasma. The encoded protein transfers phospholipids from triglyceride-rich lipoproteins to high density lipoprotein (HDL). In addition to regulating the size of HDL particles, this protein may be involved in cholesterol metabolism. At least two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18034157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLTP	NM_006227.4	c.1259T>C	p.Ile420Thr	missense_variant	Exon 14 of 16	ENST00000372431.8	NP_006218.1
PLTP	NM_182676.3	c.1103T>C	p.Ile368Thr	missense_variant	Exon 13 of 15		NP_872617.1
PLTP	NM_001242921.1	c.995T>C	p.Ile332Thr	missense_variant	Exon 12 of 14		NP_001229850.1
PLTP	NM_001242920.2	c.974T>C	p.Ile325Thr	missense_variant	Exon 12 of 14		NP_001229849.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLTP	ENST00000372431.8	c.1259T>C	p.Ile420Thr	missense_variant	Exon 14 of 16	1	NM_006227.4	ENSP00000361508.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251454 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461888 Hom.: 0 Cov.: 34 AF XY: 0.00000963 AC XY: 7 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. This variant has not been reported in the literature in individuals affected with PLTP-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 420 of the PLTP protein (p.Ile420Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.092	.;.;T;T;.
Eigen	Benign	0.0054
Eigen_PC	Benign	0.039
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;.;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.7	.;.;L;L;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.070	N;N;N;N;N
REVEL	Benign	0.19
Sift	Benign	0.67	T;T;D;D;T
Sift4G	Uncertain	0.010	D;D;D;D;D
Polyphen		0.35	B;.;P;P;.
Vest4		0.37
MVP		0.32
MPC		0.42
ClinPred		0.57	D
GERP RS		4.7
Varity_R		0.17
gMVP		0.35

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: rs760077699; hg19: chr20-44528284;