8-107251921-G-C

Variant names:

• chr8-107251921-G-C
• NM_001146.5:c.1431C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001146.5(ANGPT1):​c.1431C>G​(p.His477Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,710 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ANGPT1 NM_001146.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.662

Genes affected

ANGPT1 (HGNC:484): (angiopoietin 1) This gene encodes a secreted glycoprotein that belongs to the angiopoietin family. Members of this family play important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The protein encoded by this gene is a secreted glycoprotein that activates the receptor by inducing its tyrosine phosphorylation. It plays a critical role in mediating reciprocal interactions between the endothelium and surrounding matrix and mesenchyme and inhibits endothelial permeability. The protein also contributes to blood vessel maturation and stability, and may be involved in early development of the heart. Mutations in this gene are associated with hereditary angioedema. [provided by RefSeq, Aug 2020]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.804

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ANGPT1	NM_001146.5	c.1431C>G	p.His477Gln	missense_variant	Exon 9 of 9	ENST00000517746.6	NP_001137.2
ANGPT1	NM_001199859.3	c.1428C>G	p.His476Gln	missense_variant	Exon 9 of 9		NP_001186788.1
ANGPT1	NM_001314051.2	c.831C>G	p.His277Gln	missense_variant	Exon 8 of 8		NP_001300980.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ANGPT1	ENST00000517746.6	c.1431C>G	p.His477Gln	missense_variant	Exon 9 of 9	1	NM_001146.5	ENSP00000428340.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461710 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727160

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;.;.;T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.80	D;D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.3	L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.034	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.80
MutPred		0.49		Gain of MoRF binding (P = 0.0814);.;.;.;
MVP		0.93
MPC		2.1
ClinPred		0.97	D
GERP RS		1.6
Varity_R		0.87

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-108264149;