Genetic Variant NM_000078.3:c.-65G>A (chr16-56961915-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000078.3(CETP):c.-65G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,212,584 control chromosomes in the GnomAD database, including 169 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 115 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 54 hom. )

Consequence

CETP
NM_000078.3 upstream_gene

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0440

Publications

24 publications found

Variant links:

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]

CETP Gene-Disease associations (from GenCC):

cholesterol-ester transfer protein deficiency
Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

CETP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant 16-56961915-G-A is Benign according to our data. Variant chr16-56961915-G-A is described in ClinVar as Benign. ClinVar VariationId is 369115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0653 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000078.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETP	NM_000078.3	MANE Select	c.-65G>A		upstream_gene	N/A	NP_000069.2	P11597-1
	CETP	NM_001286085.2		c.-65G>A		upstream_gene	N/A	NP_001273014.1	A0A0S2Z3I8

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CETP	ENST00000200676.8	TSL:1 MANE Select	c.-65G>A	upstream_gene	N/A	ENSP00000200676.3	P11597-1
CETP	ENST00000379780.6	TSL:1	c.-65G>A	upstream_gene	N/A	ENSP00000369106.2	P11597-2
CETP	ENST00000858282.1		c.-65G>A	upstream_gene	N/A	ENSP00000528341.1

Frequencies

GnomAD3 genomes

AF:

0.0200

AC:

3047

AN:

152080

Hom.:

115

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0671

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0115

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0153

GnomAD4 exome

AF:

0.00233

AC:

2470

AN:

1060386

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1091

AN XY:

545364

show subpopulations

African (AFR)

AF:

0.0631

AC:

1594

AN:

25274

American (AMR)

AF:

0.00496

AC:

219

AN:

44190

Ashkenazi Jewish (ASJ)

AF:

0.00170

AC:

AN:

23580

East Asian (EAS)

AF:

0.00

AC:

AN:

37794

South Asian (SAS)

AF:

0.000231

AC:

AN:

77998

European-Finnish (FIN)

AF:

0.0000198

AC:

AN:

50614

Middle Eastern (MID)

AF:

0.00796

AC:

AN:

5024

European-Non Finnish (NFE)

AF:

0.000407

AC:

305

AN:

748714

Other (OTH)

AF:

0.00536

AC:

253

AN:

47198

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

107

214

320

427

534

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0201

AC:

3065

AN:

152198

Hom.:

115

Cov.:

AF XY:

0.0202

AC XY:

1504

AN XY:

74410

show subpopulations

African (AFR)

AF:

0.0674

AC:

2796

AN:

41500

American (AMR)

AF:

0.0114

AC:

175

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00173

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5160

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000735

AC:

AN:

68010

Other (OTH)

AF:

0.0152

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

141

282

422

563

704

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0249

Hom.:

Bravo

AF:

0.0230

Asia WGS

AF:

0.00577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hyperalphalipoproteinemia 1 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

4.5

(source)

DANN

Benign

0.76

PhyloP100

-0.044

PromoterAI

-0.11

Neutral

(source)

Mutation Taster

=300/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over