rs398122989

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_014495.4(ANGPTL3):c.883T>C(p.Phe295Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000372 in 1,610,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

ANGPTL3
NM_014495.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.88

Publications

8 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

DOCK7 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_014495.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 1-62602332-T-C is Pathogenic according to our data. Variant chr1-62602332-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 91867.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014495.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL3	NM_014495.4	MANE Select	c.883T>C	p.Phe295Leu	missense	Exon 5 of 7	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1	MANE Select	c.1683-15708A>G		intron	N/A	NP_001354490.1	Q96N67-1
DOCK7	NM_001330614.2		c.1683-15708A>G		intron	N/A	NP_001317543.1	Q96N67-6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANGPTL3	ENST00000371129.4	TSL:1 MANE Select	c.883T>C	p.Phe295Leu	missense	Exon 5 of 7	ENSP00000360170.3	Q9Y5C1
DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.1683-15708A>G		intron	N/A	ENSP00000489124.1	Q96N67-1
DOCK7	ENST00000454575.6	TSL:1	c.1683-15708A>G		intron	N/A	ENSP00000413583.2	Q96N67-2

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151610

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250870

AF XY:

0.00000737

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1459212

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

725948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33384

American (AMR)

AF:

0.00

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26024

East Asian (EAS)

AF:

0.00

AC:

AN:

39522

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1110114

Other (OTH)

AF:

0.00

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000660

AC:

AN:

151610

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74038

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15178

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67644

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000341

Hom.:

Bravo

AF:

0.0000113

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Familial hypobetalipoproteinemia 2 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.094

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

4.1

PhyloP100

5.9

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Varity_R

0.98

gMVP

0.91

Mutation Taster

=5/95

disease causing (ClinVar)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over