1-178851296-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004673.4(ANGPTL1):c.1309A>G(p.Lys437Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000372 in 1,611,158 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

ANGPTL1
NM_004673.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.26

Variant links:

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]

ANGPTL1 links:

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]

RALGPS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL1	NM_004673.4 linkuse as main transcript	c.1309A>G	p.Lys437Glu	missense_variant	6/6	ENST00000234816.7
RALGPS2	NM_152663.5 linkuse as main transcript	c.607+17746T>C		intron_variant		ENST00000367635.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL1	ENST00000234816.7 linkuse as main transcript	c.1309A>G	p.Lys437Glu	missense_variant	6/6	1	NM_004673.4	P1
RALGPS2	ENST00000367635.8 linkuse as main transcript	c.607+17746T>C		intron_variant		1	NM_152663.5	P3	Q86X27-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000806

AC:

AN:

248122

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

133960

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000391

AC:

AN:

1458942

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

725586

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152216

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.1309A>G (p.K437E) alteration is located in exon 6 (coding exon 4) of the ANGPTL1 gene. This alteration results from a A to G substitution at nucleotide position 1309, causing the lysine (K) at amino acid position 437 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.18

T;T

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.10

MetaRNN

Uncertain

0.72

D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Benign

2.0

M;M

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.62

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

1.0

D;D

Vest4

0.62

MutPred

0.58

Loss of methylation at K437 (P = 0.0069);Loss of methylation at K437 (P = 0.0069);

MVP

0.78

MPC

0.52

ClinPred

0.93

GERP RS

5.8

Varity_R

0.60

gMVP

0.85

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over