rs398122988

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_014495.4(ANGPTL3):c.363_367delCTCAA(p.Asn121LysfsTer3) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000435 in 1,552,802 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 0 hom. )

Consequence

ANGPTL3
NM_014495.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.61

Publications

9 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: Pathogenic. The variant received 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 1-62597921-GAACTC-G is Pathogenic according to our data. Variant chr1-62597921-GAACTC-G is described in ClinVar as Pathogenic. ClinVar VariationId is 91866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPTL3	NM_014495.4 link	c.363_367delCTCAA	p.Asn121LysfsTer3	frameshift_variant	Exon 1 of 7	ENST00000371129.4	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1 link	c.1683-11302_1683-11298delGAGTT		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.363_367delCTCAA	p.Asn121LysfsTer3	frameshift_variant	Exon 1 of 7	1	NM_014495.4	ENSP00000360170.3		Q9Y5C1
DOCK7	ENST00000635253.2 link	c.1683-11302_1683-11298delGAGTT		intron_variant	Intron 14 of 49	5	NM_001367561.1	ENSP00000489124.1		Q96N67-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000263

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000530

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000252

AC:

AN:

202196

AF XY:

0.000228

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.000634

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000344

Gnomad OTH exome

AF:

0.000215

GnomAD4 exome

AF:

0.000448

AC:

628

AN:

1400676

Hom.:

AF XY:

0.000413

AC XY:

286

AN XY:

692810

show subpopulations

African (AFR)

AF:

0.0000980

AC:

AN:

30624

American (AMR)

AF:

0.000388

AC:

AN:

30920

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22640

East Asian (EAS)

AF:

0.00

AC:

AN:

39084

South Asian (SAS)

AF:

0.00

AC:

AN:

74050

European-Finnish (FIN)

AF:

0.0000391

AC:

AN:

51196

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5430

European-Non Finnish (NFE)

AF:

0.000541

AC:

589

AN:

1089084

Other (OTH)

AF:

0.000382

AC:

AN:

57648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

<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:

0.000309

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41540

American (AMR)

AF:

0.000262

AC:

AN:

15246

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000530

AC:

AN:

67966

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

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:

0.000396

Hom.:

Bravo

AF:

0.000461

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ANGPTL3-related disorder

Pathogenic:1

Sep 11, 2023

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ANGPTL3 c.363_367del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn121Lysfs*3). This variant also results in a frameshift in the ANGPTL3 gene, which is transcribed on the opposite strand (c.363_367del; p.Asn121Lysfs*3). To our knowledge, this variant has not been reported in association with DOCK7-related disease. In relation to ANGPTL3, this variant has been reported in several individuals with autosomal recessive hypobetalipoproteinemia (see for example Martín-Campos et al. 2012. PubMed ID: 22155345; Blanco-Vaca et al. 2019. PubMed ID: 30782561). This variant is reported in 0.061% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-63063592-GAACTC-G). This variant is interpreted as pathogenic for autosomal recessive hypobetalipoproteinemia and likely benign for DOCK7-related disease. -

Developmental and epileptic encephalopathy, 23

Pathogenic:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Nov 11, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Asn121Lysfs*3) in the ANGPTL3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ANGPTL3 are known to be pathogenic (PMID: 22247256, 24058201). This variant is present in population databases (rs569107562, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with familial combined hypolipidemia (PMID: 22155345, 22247256, 24058201). It has also been observed to segregate with disease in related individuals. This variant is also known as p.N121Lx2. ClinVar contains an entry for this variant (Variation ID: 91866). For these reasons, this variant has been classified as Pathogenic. -

Familial hypobetalipoproteinemia 2

Pathogenic:1

Mar 22, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.6

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over