rs5742907

chr16-56982238-G-Achr16-56982238-G-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 14P and 1B. PVS1 PP3_Strong PP5_Moderate BS1_Supporting

The NM_000078.3(CETP):c.1321+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,614,016 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: CETP NM_000078.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 0.501

Genes affected

CETP (HGNC:1869): (cholesteryl ester transfer protein) The protein encoded by this gene is found in plasma, where it is involved in the transfer of cholesteryl ester from high density lipoprotein (HDL) to other lipoproteins. Defects in this gene are a cause of hyperalphalipoproteinemia 1 (HALP1). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]

ACMG classification

Verdict is Pathogenic. Variant got 13 ACMG points.

• PVS1: Splicing variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-56982238-G-A is Pathogenic according to our data. Variant chr16-56982238-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000105 (154/1461770) while in subpopulation EAS AF= 0.00292 (116/39700). AF 95% confidence interval is 0.00249. There are 1 homozygotes in gnomad4_exome. There are 73 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CETP	NM_000078.3	c.1321+1G>A		splice_donor_variant		ENST00000200676.8
CETP	NM_001286085.2	c.1141+1G>A		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CETP	ENST00000200676.8	c.1321+1G>A		splice_donor_variant		1	NM_000078.3	P1
CETP	ENST00000379780.6	c.1141+1G>A		splice_donor_variant		1
CETP	ENST00000566128.1	c.1126+1G>A		splice_donor_variant		5
CETP	ENST00000650358.1	n.1719+1G>A		splice_donor_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000963

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251424 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 154 AN: 1461770 Hom.: 1 Cov.: 34 AF XY: 0.000100 AC XY: 73 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00292

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000624 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000330 AC: 4

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hyperalphalipoproteinemia 1 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 30, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 1990	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
Cadd	Uncertain	23
Dann	Benign	0.93
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.36	N
MutationTaster	Benign	1.0	D;D;D
GERP RS		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.84
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs5742907; hg19: chr16-57016150;