rs398122987

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_014495.4(ANGPTL3):​c.439_442delAACT​(p.Asn147fs) 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 (★). 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

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:2

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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 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 criteria_provided_single_submitter, 1 stars. Variant chr1-62597996-CAACT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ANGPTL3NM_014495.4 linkc.439_442delAACT p.Asn147fs frameshift_variant Exon 1 of 7 ENST00000371129.4 NP_055310.1 Q9Y5C1
DOCK7NM_001367561.1 linkc.1683-11376_1683-11373delAGTT intron_variant Intron 14 of 49 ENST00000635253.2 NP_001354490.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ANGPTL3ENST00000371129.4 linkc.439_442delAACT p.Asn147fs frameshift_variant Exon 1 of 7 1 NM_014495.4 ENSP00000360170.3 Q9Y5C1
DOCK7ENST00000635253.2 linkc.1683-11376_1683-11373delAGTT intron_variant Intron 14 of 49 5 NM_001367561.1 ENSP00000489124.1 Q96N67-1

Frequencies

GnomAD3 genomes
AF:
0.0000921
AC:
14
AN:
152000
Hom.:
0
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2024This sequence change creates a premature translational stop signal (p.Asn147*) 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 (rs749131121, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with dyslipidemia (PMID: 22247256, 36325899). ClinVar contains an entry for this variant (Variation ID: 91865). For these reasons, this variant has been classified as Pathogenic. -
Familial hypobetalipoproteinemia 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2012- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

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

Other links and lift over

dbSNP: rs398122987; hg19: chr1-63063667; API