1-62602332-T-G

Variant names:

• chr1-62602332-T-G
• rs398122989
• NM_014495.4:c.883T>G
• ANGPTL3 p.Phe295Val

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_014495.4(ANGPTL3):​c.883T>G​(p.Phe295Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F295L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ANGPTL3 NM_014495.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88
• Publications: 0 publications found

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]

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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-62602332-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 91867.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.983

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014495.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL3	NM_014495.4	MANE Select	c.883T>G	p.Phe295Val	missense	Exon 5 of 7	NP_055310.1	Q9Y5C1
	DOCK7	NM_001367561.1	MANE Select	c.1683-15708A>C		intron	N/A	NP_001354490.1	Q96N67-1
	DOCK7	NM_001330614.2		c.1683-15708A>C		intron	N/A	NP_001317543.1	Q96N67-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL3	ENST00000371129.4	TSL:1 MANE Select	c.883T>G	p.Phe295Val	missense	Exon 5 of 7	ENSP00000360170.3	Q9Y5C1
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.1683-15708A>C		intron	N/A	ENSP00000489124.1	Q96N67-1
	DOCK7	ENST00000454575.6	TSL:1	c.1683-15708A>C		intron	N/A	ENSP00000413583.2	Q96N67-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459212 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725948

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33384

American (AMR) AF: 0.00 AC: 0 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39522

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110114

Other (OTH) AF: 0.00 AC: 0 AN: 60244

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	4.4	H
PhyloP100		5.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.99
gMVP		0.93
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398122989;

hg19: chr1-63068003;