dbSNP rs200785483: ANGPTL3:p.Glu129Lys (chr1-62597951-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014495.4(ANGPTL3):c.385G>A(p.Glu129Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000714 in 1,400,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E129G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000071 ( 0 hom. )

Consequence

ANGPTL3
NM_014495.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.23

Publications

13 publications found

Variant links:

Genes affected

ANGPTL3 (HGNC:491): (angiopoietin like 3) This gene encodes a member of a family of secreted proteins that function in angiogenesis. The encoded protein, which is expressed predominantly in the liver, is further processed into an N-terminal coiled-coil domain-containing chain and a C-terminal fibrinogen chain. The N-terminal chain is important for lipid metabolism, while the C-terminal chain may be involved in angiogenesis. Mutations in this gene cause familial hypobetalipoproteinemia type 2. [provided by RefSeq, Aug 2015]

ANGPTL3 links:

DOCK7 (HGNC:19190): (dedicator of cytokinesis 7) The protein encoded by this gene is a guanine nucleotide exchange factor (GEF) that plays a role in axon formation and neuronal polarization. The encoded protein displays GEF activity toward RAC1 and RAC3 Rho small GTPases but not toward CDC42. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]

DOCK7 Gene-Disease associations (from GenCC):

genetic developmental and epileptic encephalopathy
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
developmental and epileptic encephalopathy, 23
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

DOCK7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22588962).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL3	NM_014495.4 link	c.385G>A	p.Glu129Lys	missense_variant	Exon 1 of 7	ENST00000371129.4	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1 link	c.1683-11327C>T		intron_variant	Intron 14 of 49	ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPTL3	ENST00000371129.4 link	c.385G>A	p.Glu129Lys	missense_variant	Exon 1 of 7	1	NM_014495.4	ENSP00000360170.3		Q9Y5C1
DOCK7	ENST00000635253.2 link	c.1683-11327C>T		intron_variant	Intron 14 of 49	5	NM_001367561.1	ENSP00000489124.1		Q96N67-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000150

AC:

AN:

200326

AF XY:

0.00000917

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000714

AC:

AN:

1400622

Hom.:

Cov.:

AF XY:

0.00000577

AC XY:

AN XY:

693692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30444

American (AMR)

AF:

0.00

AC:

AN:

29572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22584

East Asian (EAS)

AF:

0.00

AC:

AN:

39054

South Asian (SAS)

AF:

0.000107

AC:

AN:

74466

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51166

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5430

European-Non Finnish (NFE)

AF:

9.17e-7

AC:

AN:

1090260

Other (OTH)

AF:

0.0000173

AC:

AN:

57646

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.092

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

M_CAP

Benign

0.013

MetaRNN

Benign

0.23

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

5.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.84

REVEL

Benign

0.13

Sift

Benign

0.33

Sift4G

Benign

0.20

Polyphen

0.58

Vest4

0.22

MutPred

0.42

Gain of ubiquitination at E129 (P = 0.0131);

MVP

0.66

MPC

0.029

ClinPred

0.65

GERP RS

4.8

PromoterAI

-0.0090

Neutral

(source)

Varity_R

0.24

gMVP

0.29

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over