rs3739390

Positions:

• chr8-6562969-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000629816.3(ANGPT2):​c.-35G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0612 in 1,550,278 control chromosomes in the GnomAD database, including 3,146 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (333 hom., cov: 29)
  • Exomes 𝑓: 0.061 (2813 hom.)
• Consequence: ANGPT2 ENST00000629816.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00600

Genes affected

ANGPT2 (HGNC:485): (angiopoietin 2) This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome. [provided by RefSeq, Aug 2020]

MCPH1 (HGNC:6954): (microcephalin 1) This gene encodes a DNA damage response protein. The encoded protein may play a role in G2/M checkpoint arrest via maintenance of inhibitory phosphorylation of cyclin-dependent kinase 1. Mutations in this gene have been associated with primary autosomal recessive microcephaly 1 and premature chromosome condensation syndrome. Alternatively spliced transcript variants have been described. [provided by RefSeq, Feb 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANGPT2	NM_001118887.2	c.-35G>C		5_prime_UTR_variant	1/9	ENST00000629816.3	NP_001112359.1
MCPH1	NM_024596.5	c.2215-58485C>G		intron_variant		ENST00000344683.10	NP_078872.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANGPT2	ENST00000629816.3	c.-35G>C		5_prime_UTR_variant	1/9	1	NM_001118887.2	ENSP00000486858	P4
MCPH1	ENST00000344683.10	c.2215-58485C>G		intron_variant		1	NM_024596.5	ENSP00000342924	P1

Frequencies

GnomAD3 genomes AF: 0.0604 AC: 9189 AN: 152132 Hom.: 332 Cov.: 29

Gnomad AFR AF: 0.0536

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0687

Gnomad ASJ AF: 0.0988

Gnomad EAS AF: 0.122

Gnomad SAS AF: 0.0845

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0561

Gnomad OTH AF: 0.0651

GnomAD3 exomes AF: 0.0668 AC: 14512 AN: 217262 Hom.: 535 AF XY: 0.0676 AC XY: 7784 AN XY: 115068

Gnomad AFR exome AF: 0.0527

Gnomad AMR exome AF: 0.0718

Gnomad ASJ exome AF: 0.0928

Gnomad EAS exome AF: 0.121

Gnomad SAS exome AF: 0.0926

Gnomad FIN exome AF: 0.0480

Gnomad NFE exome AF: 0.0535

Gnomad OTH exome AF: 0.0681

GnomAD4 exome AF: 0.0613 AC: 85672 AN: 1398028 Hom.: 2813 Cov.: 32 AF XY: 0.0620 AC XY: 42528 AN XY: 685772

Gnomad4 AFR exome AF: 0.0581

Gnomad4 AMR exome AF: 0.0695

Gnomad4 ASJ exome AF: 0.0877

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.0912

Gnomad4 FIN exome AF: 0.0448

Gnomad4 NFE exome AF: 0.0571

Gnomad4 OTH exome AF: 0.0683

GnomAD4 genome AF: 0.0604 AC: 9198 AN: 152250 Hom.: 333 Cov.: 29 AF XY: 0.0615 AC XY: 4580 AN XY: 74440

Gnomad4 AFR AF: 0.0535

Gnomad4 AMR AF: 0.0690

Gnomad4 ASJ AF: 0.0988

Gnomad4 EAS AF: 0.121

Gnomad4 SAS AF: 0.0850

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0561

Gnomad4 OTH AF: 0.0649

Alfa AF: 0.0586 Hom.: 57

Bravo AF: 0.0613

Asia WGS AF: 0.0770 AC: 268 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	12
DANN	Benign	0.66

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

Other links and lift over

dbSNP: rs3739390; hg19: chr8-6420490; COSMIC: COSV57336310;