1-62597951-G-A

Variant names:

• chr1-62597951-G-A
• rs200785483
• NM_014495.4:c.385G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014495.4(ANGPTL3):​c.385G>A​(p.Glu129Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000714 in 1,400,622 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. E129G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: ANGPTL3 NM_014495.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 13 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22588962).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL3	NM_014495.4	MANE Select	c.385G>A	p.Glu129Lys	missense	Exon 1 of 7	NP_055310.1
	DOCK7	NM_001367561.1	MANE Select	c.1683-11327C>T		intron	N/A	NP_001354490.1
	DOCK7	NM_001330614.2		c.1683-11327C>T		intron	N/A	NP_001317543.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL3	ENST00000371129.4	TSL:1 MANE Select	c.385G>A	p.Glu129Lys	missense	Exon 1 of 7	ENSP00000360170.3
	DOCK7	ENST00000635253.2	TSL:5 MANE Select	c.1683-11327C>T		intron	N/A	ENSP00000489124.1
	DOCK7	ENST00000454575.6	TSL:1	c.1683-11327C>T		intron	N/A	ENSP00000413583.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000150 AC: 3 AN: 200326 AF XY: 0.00000917

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000714 AC: 10 AN: 1400622 Hom.: 0 Cov.: 31 AF XY: 0.00000577 AC XY: 4 AN XY: 693692

African (AFR) AF: 0.00 AC: 0 AN: 30444

American (AMR) AF: 0.00 AC: 0 AN: 29572

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22584

East Asian (EAS) AF: 0.00 AC: 0 AN: 39054

South Asian (SAS) AF: 0.000107 AC: 8 AN: 74466

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5430

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090260

Other (OTH) AF: 0.0000173 AC: 1 AN: 57646

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.092	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.13
Sift	Benign	0.33	T
Sift4G	Benign	0.20	T
Polyphen		0.58	P
Vest4		0.22
MutPred		0.42		Gain of ubiquitination at E129 (P = 0.0131)
MVP		0.66
MPC		0.029
ClinPred		0.65	D
GERP RS		4.8
PromoterAI		-0.0090	Neutral
Varity_R		0.24
gMVP		0.29
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200785483; hg19: chr1-63063622;