1-178852705-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_004673.4(ANGPTL1):c.1266C>T(p.Asp422=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,613,540 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.014 (51 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (46 hom.)
• Consequence: ANGPTL1 NM_004673.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.06

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

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 1-178852705-G-A is Benign according to our data. Variant chr1-178852705-G-A is described in ClinVar as [Benign]. Clinvar id is 784965.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=2.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.014 (2133/152160) while in subpopulation AFR AF= 0.0483 (2003/41510). AF 95% confidence interval is 0.0465. There are 51 homozygotes in gnomad4. There are 956 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ANGPTL1	NM_004673.4	c.1266C>T	p.Asp422=	synonymous_variant	5/6	ENST00000234816.7
RALGPS2	NM_152663.5	c.607+19155G>A		intron_variant		ENST00000367635.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ANGPTL1	ENST00000234816.7	c.1266C>T	p.Asp422=	synonymous_variant	5/6	1	NM_004673.4	P1
RALGPS2	ENST00000367635.8	c.607+19155G>A		intron_variant		1	NM_152663.5	P3

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2130 AN: 152042 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00557

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0100

GnomAD3 exomes AF: 0.00363 AC: 912 AN: 250912 Hom.: 19 AF XY: 0.00268 AC XY: 364 AN XY: 135602

Gnomad AFR exome AF: 0.0473

Gnomad AMR exome AF: 0.00273

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: 0.000326

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.00159 AC: 2327 AN: 1461380 Hom.: 46 Cov.: 31 AF XY: 0.00140 AC XY: 1021 AN XY: 726956

Gnomad4 AFR exome AF: 0.0495

Gnomad4 AMR exome AF: 0.00342

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000282

Gnomad4 OTH exome AF: 0.00305

GnomAD4 genome AF: 0.0140 AC: 2133 AN: 152160 Hom.: 51 Cov.: 32 AF XY: 0.0129 AC XY: 956 AN XY: 74382

Gnomad4 AFR AF: 0.0483

Gnomad4 AMR AF: 0.00556

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00993

Alfa AF: 0.00822 Hom.: 19

Bravo AF: 0.0160

Asia WGS AF: 0.00202 AC: 8 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000652

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

Feb 16, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	7.4
Dann	Benign	0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs34483360; hg19: chr1-178821840;