rs5881

Variant names:

• chr16-56978100-G-A
• rs5881
• NM_000078.3:c.991G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_000078.3(CETP):​c.991G>A​(p.Gly331Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000178 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G331V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: CETP NM_000078.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.193

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004303843).
• BP6: Variant 16-56978100-G-A is Benign according to our data. Variant chr16-56978100-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 319986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-56978100-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000243 (37/152284) while in subpopulation EAS AF = 0.00289 (15/5188). AF 95% confidence interval is 0.00178. There are 0 homozygotes in GnomAd4. There are 25 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CETP	NM_000078.3	c.991G>A	p.Gly331Ser	missense_variant	Exon 11 of 16	ENST00000200676.8	NP_000069.2
CETP	NM_001286085.2	c.811G>A	p.Gly271Ser	missense_variant	Exon 10 of 15		NP_001273014.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CETP	ENST00000200676.8	c.991G>A	p.Gly331Ser	missense_variant	Exon 11 of 16	1	NM_000078.3	ENSP00000200676.3
CETP	ENST00000379780.6	c.811G>A	p.Gly271Ser	missense_variant	Exon 10 of 15	1		ENSP00000369106.2
CETP	ENST00000566128.1	c.796G>A	p.Gly266Ser	missense_variant	Exon 11 of 16	5		ENSP00000456276.1
CETP	ENST00000650358.1	n.1389G>A		non_coding_transcript_exon_variant	Exon 1 of 5

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00288

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000469 AC: 118 AN: 251332 AF XY: 0.000427

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00500

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000172 AC: 251 AN: 1461818 Hom.: 1 Cov.: 32 AF XY: 0.000169 AC XY: 123 AN XY: 727196

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33480

Gnomad4 AMR exome AF: 0.000157 AC: 7 AN: 44724

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26134

Gnomad4 EAS exome AF: 0.00214 AC: 85 AN: 39698

Gnomad4 SAS exome AF: 0.000255 AC: 22 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53410

Gnomad4 NFE exome AF: 0.000108 AC: 120 AN: 1111966

Gnomad4 Remaining exome AF: 0.000281 AC: 17 AN: 60396

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25 AN XY: 74456

Gnomad4 AFR AF: 0.0000722 AC: 0.0000721987 AN: 0.0000721987

Gnomad4 AMR AF: 0.000196 AC: 0.000196207 AN: 0.000196207

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00289 AC: 0.00289129 AN: 0.00289129

Gnomad4 SAS AF: 0.000414 AC: 0.000414079 AN: 0.000414079

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000206 AC: 0.000205804 AN: 0.000205804

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000307 Hom.: 0

Bravo AF: 0.000351

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000486 AC: 59

EpiCase AF: 0.000273

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CETP-related disorder Benign:1

Jun 07, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Dec 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hyperalphalipoproteinemia 1 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.68	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.76
DANN	Benign	0.36
DEOGEN2	Benign	0.10	T;.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.010	N
LIST_S2	Benign	0.65	T;T;T
MetaRNN	Benign	0.0043	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.3	L;.;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.78	N;N;N
REVEL	Benign	0.0040
Sift	Benign	0.57	T;T;T
Sift4G	Benign	0.27	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.098
MVP		0.15
MPC		0.13
ClinPred		0.012	T
GERP RS		-5.2
Varity_R		0.077
gMVP		0.19
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5881; hg19: chr16-57012012;