rs5883

Positions:

• chr16-56973441-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000078.3(CETP):​c.861C>T​(p.Phe287Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0536 in 1,614,184 control chromosomes in the GnomAD database, including 2,687 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (399 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2288 hom.)
• Consequence: CETP NM_000078.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.649

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-56973441-C-T is Benign according to our data. Variant chr16-56973441-C-T is described in ClinVar as [Benign]. Clinvar id is 319984.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56973441-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.649 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CETP	NM_000078.3	c.861C>T	p.Phe287Phe	synonymous_variant	9/16	ENST00000200676.8	NP_000069.2
CETP	NM_001286085.2	c.750+1358C>T		intron_variant			NP_001273014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CETP	ENST00000200676.8	c.861C>T	p.Phe287Phe	synonymous_variant	9/16	1	NM_000078.3	ENSP00000200676.3
CETP	ENST00000379780.6	c.750+1358C>T		intron_variant		1		ENSP00000369106.2
CETP	ENST00000566128.1	c.666C>T	p.Phe222Phe	synonymous_variant	9/16	5		ENSP00000456276.1

Frequencies

GnomAD3 genomes AF: 0.0648 AC: 9861 AN: 152190 Hom.: 399 Cov.: 32

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0403

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0368

Gnomad FIN AF: 0.0354

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0533

Gnomad OTH AF: 0.0574

GnomAD3 exomes AF: 0.0513 AC: 12897 AN: 251464 Hom.: 417 AF XY: 0.0500 AC XY: 6796 AN XY: 135908

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.0294

Gnomad ASJ exome AF: 0.129

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.0363

Gnomad FIN exome AF: 0.0396

Gnomad NFE exome AF: 0.0568

Gnomad OTH exome AF: 0.0638

GnomAD4 exome AF: 0.0525 AC: 76707 AN: 1461876 Hom.: 2288 Cov.: 33 AF XY: 0.0520 AC XY: 37795 AN XY: 727244

Gnomad4 AFR exome AF: 0.111

Gnomad4 AMR exome AF: 0.0308

Gnomad4 ASJ exome AF: 0.124

Gnomad4 EAS exome AF: 0.000453

Gnomad4 SAS exome AF: 0.0380

Gnomad4 FIN exome AF: 0.0441

Gnomad4 NFE exome AF: 0.0532

Gnomad4 OTH exome AF: 0.0536

GnomAD4 genome AF: 0.0648 AC: 9864 AN: 152308 Hom.: 399 Cov.: 32 AF XY: 0.0611 AC XY: 4554 AN XY: 74486

Gnomad4 AFR AF: 0.106

Gnomad4 AMR AF: 0.0402

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0375

Gnomad4 FIN AF: 0.0354

Gnomad4 NFE AF: 0.0533

Gnomad4 OTH AF: 0.0587

Alfa AF: 0.0598 Hom.: 679

Bravo AF: 0.0680

Asia WGS AF: 0.0260 AC: 89 AN: 3478

EpiCase AF: 0.0545

EpiControl AF: 0.0593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 17, 2018	This variant is associated with the following publications: (PMID: 28008009, 22403620, 24393849) -

Hyperalphalipoproteinemia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.5
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs5883; hg19: chr16-57007353; COSMIC: COSV52362633; COSMIC: COSV52362633;