20-879815-A-T

Variant names:

• chr20-879815-A-T
• NM_015985.4:c.985T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_015985.4(ANGPT4):​c.985T>A​(p.Trp329Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ANGPT4 NM_015985.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.04
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

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.985T>A	p.Trp329Arg	missense	Exon 6 of 9	NP_057069.1	Q9Y264-1
	ANGPT4	NM_001322809.2		c.985T>A	p.Trp329Arg	missense	Exon 6 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.985T>A	p.Trp329Arg	missense	Exon 6 of 9	ENSP00000371347.3	Q9Y264-1
	ANGPT4	ENST00000878109.1		c.829T>A	p.Trp277Arg	missense	Exon 5 of 8	ENSP00000548168.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		9.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-13	D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.92		Gain of disorder (P = 0.0017)
MVP		0.83
MPC		1.0
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.96
Mutation Taster		=30/70	disease causing

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: chr20-860458;