NM_015985.4:c.1187A>G

Variant names:

• chr20-878194-T-C
• NM_015985.4:c.1187A>G

Variant summary

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

The NM_015985.4(ANGPT4):​c.1187A>G​(p.His396Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,494 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ANGPT4 NM_015985.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00900
• Publications: 0 publications found

Genes affected

ANGPT4 (HGNC:487): (angiopoietin 4) Angiopoietins are proteins with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The mechanism by which they contribute to angiogenesis is thought to involve regulation of endothelial cell interactions with supporting perivascular cells. The protein encoded by this gene functions as an agonist and is an angiopoietin. [provided by RefSeq, Jul 2008]

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=0.2027705).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015985.4. 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
	ANGPT4	NM_015985.4	MANE Select	c.1187A>G	p.His396Arg	missense	Exon 7 of 9	NP_057069.1	Q9Y264-1
	ANGPT4	NM_001322809.2		c.1187A>G	p.His396Arg	missense	Exon 7 of 8	NP_001309738.1	Q9Y264-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPT4	ENST00000381922.5	TSL:1 MANE Select	c.1187A>G	p.His396Arg	missense	Exon 7 of 9	ENSP00000371347.3	Q9Y264-1
	ANGPT4	ENST00000878109.1		c.1031A>G	p.His344Arg	missense	Exon 6 of 8	ENSP00000548168.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453494 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721166

African (AFR) AF: 0.00 AC: 0 AN: 33356

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.00 AC: 0 AN: 39442

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5626

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105156

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	5.4
DANN	Benign	0.18
DEOGEN2	Benign	0.013	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0078	N
LIST_S2	Benign	0.23	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.10	N
PhyloP100		0.0090
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.19
Sift	Benign	0.59	T
Sift4G	Benign	0.97	T
Polyphen		0.036	B
Vest4		0.062
MutPred		0.40		Gain of catalytic residue at H396 (P = 0.0565)
MVP		0.43
MPC		0.25
ClinPred		0.063	T
GERP RS		-3.8
Varity_R		0.12
gMVP		0.33
Mutation Taster		=88/12	polymorphism

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

Other links and lift over

hg19: chr20-858837;