NM_004673.4:c.1468A>T

Variant names:

• chr1-178851137-T-A
• rs751143263
• NM_004673.4:c.1468A>T

Variant summary

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

The NM_004673.4(ANGPTL1):​c.1468A>T​(p.Ile490Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,460,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I490T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: ANGPTL1 NM_004673.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

ANGPTL1 (HGNC:489): (angiopoietin like 1) 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. The protein encoded by this gene is another member of the angiopoietin family that is widely expressed in adult tissues with mRNA levels highest in highly vascularized tissues. This protein was found to be a secretory protein that does not act as an endothelial cell mitogen in vitro. [provided by RefSeq, Jul 2008]

RALGPS2 (HGNC:30279): (Ral GEF with PH domain and SH3 binding motif 2) Predicted to enable guanyl-nucleotide exchange factor activity. Predicted to be involved in regulation of Ral protein signal transduction; regulation of catalytic activity; and small GTPase mediated 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, 0.818

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004673.4. 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
	ANGPTL1	NM_004673.4	MANE Select	c.1468A>T	p.Ile490Phe	missense	Exon 6 of 6	NP_004664.1	O95841
	RALGPS2	NM_152663.5	MANE Select	c.607+17587T>A		intron	N/A	NP_689876.2
	ANGPTL1	NM_001376763.1		c.1468A>T	p.Ile490Phe	missense	Exon 5 of 5	NP_001363692.1	O95841

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ANGPTL1	ENST00000234816.7	TSL:1 MANE Select	c.1468A>T	p.Ile490Phe	missense	Exon 6 of 6	ENSP00000234816.2	O95841
	ANGPTL1	ENST00000367629.1	TSL:1	c.1468A>T	p.Ile490Phe	missense	Exon 5 of 5	ENSP00000356601.1	O95841
	RALGPS2	ENST00000367635.8	TSL:1 MANE Select	c.607+17587T>A		intron	N/A	ENSP00000356607.3	Q86X27-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1460230 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726334

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 85812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111404

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

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	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.058	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.036	D
MutationAssessor	Benign	0.99	L
PhyloP100		8.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.39		Loss of MoRF binding (P = 0.1029)
MVP		0.84
MPC		0.57
ClinPred		0.83	D
GERP RS		6.2
Varity_R		0.34
gMVP		0.74
Mutation Taster		=42/58	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: rs751143263; hg19: chr1-178820272;