chr19-44919176-G-T

Position:

• chr19-44919176-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001645.5(APOC1):​c.198G>T​(p.Glu66Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000582 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: APOC1 NM_001645.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.13

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.033067703).
• BP6: Variant 19-44919176-G-T is Benign according to our data. Variant chr19-44919176-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3127992.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
APOC1	NM_001645.5	c.198G>T	p.Glu66Asp	missense_variant	4/4	ENST00000592535.6	NP_001636.1
APOC1	NM_001379687.1	c.343G>T	p.Val115Leu	missense_variant	4/4		NP_001366616.1
APOC1	NM_001321065.2	c.198G>T	p.Glu66Asp	missense_variant	4/4		NP_001307994.1
APOC1	NM_001321066.2	c.198G>T	p.Glu66Asp	missense_variant	5/5		NP_001307995.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
APOC1	ENST00000592535.6	c.198G>T	p.Glu66Asp	missense_variant	4/4	1	NM_001645.5	ENSP00000468276	P1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152202 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251150 Hom.: 0 AF XY: 0.0000516 AC XY: 7 AN XY: 135730

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000793

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000527 AC: 77 AN: 1461430 Hom.: 0 Cov.: 30 AF XY: 0.0000509 AC XY: 37 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000522

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152320 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74474

Gnomad4 AFR AF: 0.000216

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.017
DANN	Benign	0.10
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.15	.;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.033	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.41	T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.052
MutPred		0.40		Loss of ubiquitination at K63 (P = 0.092);Loss of ubiquitination at K63 (P = 0.092);Loss of ubiquitination at K63 (P = 0.092);
MVP		0.14
MPC		0.14
ClinPred		0.015	T
GERP RS		-5.5
Varity_R		0.14
gMVP		0.076

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: rs545479140; hg19: chr19-45422433;