Genetic Variant NM_001645.5:c.58+240C>T (chr19-44915189-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001645.5(APOC1):c.58+240C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00408 in 568,182 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.011 ( 23 hom., cov: 31)

Exomes 𝑓: 0.0016 ( 10 hom. )

Consequence

APOC1
NM_001645.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0510

Publications

9 publications found

Variant links:

Genes affected

APOC1 (HGNC:607): (apolipoprotein C1) This gene encodes a member of the apolipoprotein C1 family. This gene is expressed primarily in the liver, and it is activated when monocytes differentiate into macrophages. The encoded protein plays a central role in high density lipoprotein (HDL) and very low density lipoprotein (VLDL) metabolism. This protein has also been shown to inhibit cholesteryl ester transfer protein in plasma. A pseudogene of this gene is located 4 kb downstream in the same orientation, on the same chromosome. This gene is mapped to chromosome 19, where it resides within a apolipoprotein gene cluster. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Sep 2016]

APOC1 links:

ENSG00000280087 (HGNC:):

ENSG00000280087 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1647/152198) while in subpopulation AFR AF = 0.0371 (1540/41526). AF 95% confidence interval is 0.0355. There are 23 homozygotes in GnomAd4. There are 783 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
APOC1	NM_001645.5 link	c.58+240C>T	intron_variant	Intron 2 of 3	ENST00000592535.6	NP_001636.1	P02654A0A024R0T8
APOC1	NM_001379687.1 link	c.58+240C>T	intron_variant	Intron 2 of 3		NP_001366616.1
APOC1	NM_001321065.2 link	c.58+240C>T	intron_variant	Intron 2 of 3		NP_001307994.1	P02654A0A024R0T8
APOC1	NM_001321066.2 link	c.58+240C>T	intron_variant	Intron 3 of 4		NP_001307995.1	P02654A0A024R0T8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
APOC1	ENST00000592535.6 link	c.58+240C>T		intron_variant	Intron 2 of 3	1	NM_001645.5	ENSP00000468276.2		P02654K7ERI9

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1645

AN:

152080

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0371

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00374

Gnomad ASJ

AF:

0.00576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00436

AC:

261

AN:

59834

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.0390

Gnomad AMR exome

AF:

0.00137

Gnomad ASJ exome

AF:

0.0102

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000252

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.00161

AC:

670

AN:

415984

Hom.:

Cov.:

AF XY:

0.00138

AC XY:

303

AN XY:

219758

show subpopulations

African (AFR)

AF:

0.0357

AC:

414

AN:

11608

American (AMR)

AF:

0.00206

AC:

AN:

17990

Ashkenazi Jewish (ASJ)

AF:

0.00855

AC:

109

AN:

12756

East Asian (EAS)

AF:

0.00

AC:

AN:

28114

South Asian (SAS)

AF:

0.0000226

AC:

AN:

44210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27468

Middle Eastern (MID)

AF:

0.000566

AC:

AN:

1768

European-Non Finnish (NFE)

AF:

0.000125

AC:

AN:

248258

Other (OTH)

AF:

0.00323

AC:

AN:

23812

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0108

AC:

1647

AN:

152198

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

783

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.0371

AC:

1540

AN:

41526

American (AMR)

AF:

0.00373

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00576

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000235

AC:

AN:

68012

Other (OTH)

AF:

0.00664

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00676

Hom.:

Bravo

AF:

0.0118

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.86

PhyloP100

0.051

PromoterAI

-0.082

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over