rs398122987

chr1-62597996-CAACT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_014495.4(ANGPTL3):c.439_442del(p.Asn147Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,567,704 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: ANGPTL3 NM_014495.4 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 11 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 1-62597996-CAACT-C is Pathogenic according to our data. Variant chr1-62597996-CAACT-C is described in ClinVar as [Pathogenic]. Clinvar id is 91865.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-62597996-CAACT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL3	NM_014495.4	c.439_442del	p.Asn147Ter	frameshift_variant	1/7	ENST00000371129.4
DOCK7	NM_001367561.1	c.1683-11376_1683-11373del		intron_variant		ENST00000635253.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL3	ENST00000371129.4	c.439_442del	p.Asn147Ter	frameshift_variant	1/7	1	NM_014495.4	P1
DOCK7	ENST00000635253.2	c.1683-11376_1683-11373del		intron_variant		5	NM_001367561.1

Frequencies

GnomAD3 genomes AF: 0.0000921 AC: 14 AN: 152000 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000172 AC: 36 AN: 208860 Hom.: 0 AF XY: 0.000192 AC XY: 22 AN XY: 114468

Gnomad AFR exome AF: 0.0000684

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000635

Gnomad SAS exome AF: 0.000385

Gnomad FIN exome AF: 0.000101

Gnomad NFE exome AF: 0.000217

Gnomad OTH exome AF: 0.000208

GnomAD4 exome AF: 0.000209 AC: 296 AN: 1415586 Hom.: 1 AF XY: 0.000219 AC XY: 154 AN XY: 703506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000330

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000204

Gnomad4 SAS exome AF: 0.000299

Gnomad4 FIN exome AF: 0.0000577

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000206

GnomAD4 genome AF: 0.0000920 AC: 14 AN: 152118 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74362

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.0000907

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Familial hypobetalipoproteinemia 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2012

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Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs398122987; hg19: chr1-63063667;