rs398122988

chr1-62597921-GAACTC-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_014495.4(ANGPTL3):c.363_367del(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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.61

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]

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]

ACMG classification

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	UniProt
ANGPTL3	NM_014495.4	c.363_367del	p.Asn121LysfsTer3	frameshift_variant	1/7	ENST00000371129.4
DOCK7	NM_001367561.1	c.1683-11302_1683-11298del		intron_variant		ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL3	ENST00000371129.4	c.363_367del	p.Asn121LysfsTer3	frameshift_variant	1/7	1	NM_014495.4	P1
DOCK7	ENST00000635253.2	c.1683-11302_1683-11298del		intron_variant		5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152008 Hom.: 0 Cov.: 32

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: 51 AN: 202196 Hom.: 0 AF XY: 0.000228 AC XY: 25 AN XY: 109456

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.: 0 AF XY: 0.000413 AC XY: 286 AN XY: 692810

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: 47 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74378

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.: 0

Bravo AF: 0.000461

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

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

Invitae

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122988; hg19: chr1-63063592;