10-33185716-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_003873.7(NRP1):c.2343C>T(p.Phe781=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0362 in 1,612,560 control chromosomes in the GnomAD database, including 1,319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.030 (123 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1196 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0390

Genes affected

NRP1 (HGNC:8004): (neuropilin 1) This gene encodes one of two neuropilins, which contain specific protein domains which allow them to participate in several different types of signaling pathways that control cell migration. Neuropilins contain a large N-terminal extracellular domain, made up of complement-binding, coagulation factor V/VIII, and meprin domains. These proteins also contains a short membrane-spanning domain and a small cytoplasmic domain. Neuropilins bind many ligands and various types of co-receptors; they affect cell survival, migration, and attraction. Some of the ligands and co-receptors bound by neuropilins are vascular endothelial growth factor (VEGF) and semaphorin family members. This protein has also been determined to act as a co-receptor for SARS-CoV-2 (which causes COVID-19) to infect host cells. [provided by RefSeq, Nov 2020]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 10-33185716-G-A is Benign according to our data. Variant chr10-33185716-G-A is described in ClinVar as [Benign]. Clinvar id is 3055862.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.039 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0303 (4617/152202) while in subpopulation NFE AF= 0.0393 (2673/68004). AF 95% confidence interval is 0.0381. There are 123 homozygotes in gnomad4. There are 2383 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 4617 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.2343C>T	p.Phe781=	synonymous_variant	15/17	ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.2343C>T	p.Phe781=	synonymous_variant	15/17	1	NM_003873.7	P3
NRP1	ENST00000395995.5	c.2343C>T	p.Phe781=	synonymous_variant	15/16	1		A2
NRP1	ENST00000374875.5	c.1779C>T	p.Phe593=	synonymous_variant	14/16	1
NRP1	ENST00000265371.8	c.2343C>T	p.Phe781=	synonymous_variant	16/18	5		P3

Frequencies

GnomAD3 genomes AF: 0.0304 AC: 4617 AN: 152084 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00678

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0273

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0221

GnomAD3 exomes AF: 0.0343 AC: 8632 AN: 251336 Hom.: 211 AF XY: 0.0362 AC XY: 4913 AN XY: 135844

Gnomad AFR exome AF: 0.00615

Gnomad AMR exome AF: 0.0223

Gnomad ASJ exome AF: 0.0157

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0330

Gnomad FIN exome AF: 0.0824

Gnomad NFE exome AF: 0.0406

Gnomad OTH exome AF: 0.0313

GnomAD4 exome AF: 0.0368 AC: 53783 AN: 1460358 Hom.: 1196 Cov.: 30 AF XY: 0.0373 AC XY: 27078 AN XY: 726622

Gnomad4 AFR exome AF: 0.00595

Gnomad4 AMR exome AF: 0.0234

Gnomad4 ASJ exome AF: 0.0164

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.0339

Gnomad4 FIN exome AF: 0.0774

Gnomad4 NFE exome AF: 0.0387

Gnomad4 OTH exome AF: 0.0321

GnomAD4 genome AF: 0.0303 AC: 4617 AN: 152202 Hom.: 123 Cov.: 32 AF XY: 0.0320 AC XY: 2383 AN XY: 74400

Gnomad4 AFR AF: 0.00679

Gnomad4 AMR AF: 0.0272

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.0828

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0218

Alfa AF: 0.0354 Hom.: 46

Bravo AF: 0.0249

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0359

EpiControl AF: 0.0371

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
Cadd	Benign	12
Dann	Benign	0.67

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: rs61760432; hg19: chr10-33474644;