20-874330-T-G

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_015985.4(ANGPT4):c.1305A>C(p.Ser435=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00607 in 1,614,190 control chromosomes in the GnomAD database, including 179 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (140 hom.)
• Consequence: ANGPT4 NM_015985.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.31

Genes affected

ANGPT4 (HGNC:487): (angiopoietin 4) Angiopoietins are proteins with important roles in vascular development and angiogenesis. All angiopoietins bind with similar affinity to an endothelial cell-specific tyrosine-protein kinase receptor. The mechanism by which they contribute to angiogenesis is thought to involve regulation of endothelial cell interactions with supporting perivascular cells. The protein encoded by this gene functions as an agonist and is an angiopoietin. [provided by RefSeq, Jul 2008]

LOC124904854 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 20-874330-T-G is Benign according to our data. Variant chr20-874330-T-G is described in ClinVar as [Benign]. Clinvar id is 771934.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-3.31 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.016 (2443/152312) while in subpopulation AFR AF= 0.0397 (1649/41562). AF 95% confidence interval is 0.0381. There are 39 homozygotes in gnomad4. There are 1226 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 38 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPT4	NM_015985.4	c.1305A>C	p.Ser435=	synonymous_variant	8/9	ENST00000381922.5
LOC124904854	XR_007067485.1	n.1329+189T>G		intron_variant, non_coding_transcript_variant
ANGPT4	XM_011529239.4	c.1149A>C	p.Ser383=	synonymous_variant	7/8
ANGPT4	NM_001322809.2	c.1221-1210A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPT4	ENST00000381922.5	c.1305A>C	p.Ser435=	synonymous_variant	8/9	1	NM_015985.4	P1

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2438 AN: 152194 Hom.: 38 Cov.: 32

Gnomad AFR AF: 0.0396

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0651

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.0220

GnomAD3 exomes AF: 0.00968 AC: 2434 AN: 251420 Hom.: 45 AF XY: 0.00853 AC XY: 1159 AN XY: 135886

Gnomad AFR exome AF: 0.0380

Gnomad AMR exome AF: 0.00894

Gnomad ASJ exome AF: 0.0703

Gnomad EAS exome AF: 0.00337

Gnomad SAS exome AF: 0.00121

Gnomad FIN exome AF: 0.0107

Gnomad NFE exome AF: 0.00338

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00504 AC: 7363 AN: 1461878 Hom.: 140 Cov.: 33 AF XY: 0.00485 AC XY: 3529 AN XY: 727244

Gnomad4 AFR exome AF: 0.0411

Gnomad4 AMR exome AF: 0.00928

Gnomad4 ASJ exome AF: 0.0692

Gnomad4 EAS exome AF: 0.00290

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00940

Gnomad4 NFE exome AF: 0.00192

Gnomad4 OTH exome AF: 0.0127

GnomAD4 genome AF: 0.0160 AC: 2443 AN: 152312 Hom.: 39 Cov.: 32 AF XY: 0.0165 AC XY: 1226 AN XY: 74484

Gnomad4 AFR AF: 0.0397

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0651

Gnomad4 EAS AF: 0.00521

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.00256

Gnomad4 OTH AF: 0.0213

Alfa AF: 0.0125 Hom.: 17

Bravo AF: 0.0173

Asia WGS AF: 0.00982 AC: 34 AN: 3478

EpiCase AF: 0.00349

EpiControl AF: 0.00480

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.43
Dann	Benign	0.36

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: rs62641668; hg19: chr20-854973;