rs398122988

Positions:

chr1-62597921-GAACTC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014495.4(ANGPTL3):c.363_367delCTCAA(p.Asn121fs) 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

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 links:

DOCK7 (HGNC:):

DOCK7 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

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

PM2

Very rare variant in population databases, with high coverage;

PP5

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPTL3	NM_014495.4 linkuse as main transcript	c.363_367delCTCAA	p.Asn121fs	frameshift_variant	1/7	ENST00000371129.4	NP_055310.1	Q9Y5C1
DOCK7	NM_001367561.1 linkuse as main transcript	c.1683-11302_1683-11298delGAGTT		intron_variant		ENST00000635253.2	NP_001354490.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPTL3	ENST00000371129.4 linkuse as main transcript	c.363_367delCTCAA	p.Asn121fs	frameshift_variant	1/7	1	NM_014495.4	ENSP00000360170.3		Q9Y5C1
DOCK7	ENST00000635253.2 linkuse as main transcript	c.1683-11302_1683-11298delGAGTT		intron_variant		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

GnomAD3 exomes

AF:

0.000252

AC:

AN:

202196

Hom.:

AF XY:

0.000228

AC XY:

AN XY:

109456

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000980

Gnomad4 AMR exome

AF:

0.000388

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000391

Gnomad4 NFE exome

AF:

0.000541

Gnomad4 OTH exome

AF:

0.000382

GnomAD4 genome

AF:

0.000309

AC:

AN:

152126

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000530

Gnomad4 OTH

AF:

0.000474

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

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 29, 2021

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 22, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over