9-127108286-C-A

Variant names:

• chr9-127108286-C-A
• rs752053998
• NM_012098.3:c.446G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012098.3(ANGPTL2):​c.446G>T​(p.Arg149Leu) 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. 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. R149Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 30)
• Consequence: ANGPTL2 NM_012098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

Genes affected

ANGPTL2 (HGNC:490): (angiopoietin like 2) Angiopoietins are members of the vascular endothelial growth factor family and the only known growth factors largely specific for vascular endothelium. Angiopoietin-1, angiopoietin-2, and angiopoietin-4 participate in the formation of blood vessels. ANGPTL2 protein is a secreted glycoprotein with homology to the angiopoietins and may exert a function on endothelial cells through autocrine or paracrine action. [provided by RefSeq, Jul 2008]

RALGPS1 (HGNC:16851): (Ral GEF with PH domain and SH3 binding motif 1) Enables guanyl-nucleotide exchange factor activity. Involved in regulation of Ral protein signal transduction. Predicted to be located in cytoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012098.3. 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
	ANGPTL2	NM_012098.3	MANE Select	c.446G>T	p.Arg149Leu	missense	Exon 2 of 5	NP_036230.1	Q9UKU9-1
	RALGPS1	NM_014636.3	MANE Select	c.610+38930C>A		intron	N/A	NP_055451.1	Q5JS13-1
	RALGPS1	NM_001322325.2		c.610+38930C>A		intron	N/A	NP_001309254.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL2	ENST00000373425.8	TSL:1 MANE Select	c.446G>T	p.Arg149Leu	missense	Exon 2 of 5	ENSP00000362524.3	Q9UKU9-1
	RALGPS1	ENST00000259351.10	TSL:1 MANE Select	c.610+38930C>A		intron	N/A	ENSP00000259351.5	Q5JS13-1
	RALGPS1	ENST00000373434.5	TSL:1	c.610+38930C>A		intron	N/A	ENSP00000362533.1	Q5JS13-2

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.29
Sift	Benign	0.21	T
Sift4G	Uncertain	0.047	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.38		Loss of ubiquitination at K148 (P = 0.0573)
MVP		0.69
MPC		1.3
ClinPred		0.99	D
GERP RS		5.2
Varity_R		0.33
gMVP		0.51
Mutation Taster		=22/78	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

dbSNP: rs752053998; hg19: chr9-129870565;