10-33185710-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003873.7(NRP1):c.2349C>A(p.Gly783=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00429 in 1,613,266 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G783G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0030 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (19 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.13

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 10-33185710-G-T is Benign according to our data. Variant chr10-33185710-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 770764.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS2: High AC in GnomAd at 452 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.2349C>A	p.Gly783=	synonymous_variant	15/17	ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.2349C>A	p.Gly783=	synonymous_variant	15/17	1	NM_003873.7	P3
NRP1	ENST00000395995.5	c.2349C>A	p.Gly783=	synonymous_variant	15/16	1		A2
NRP1	ENST00000374875.5	c.1785C>A	p.Gly595=	synonymous_variant	14/16	1
NRP1	ENST00000265371.8	c.2349C>A	p.Gly783=	synonymous_variant	16/18	5		P3

Frequencies

GnomAD3 genomes AF: 0.00297 AC: 452 AN: 152070 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00462

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00264 AC: 663 AN: 251338 Hom.: 1 AF XY: 0.00277 AC XY: 376 AN XY: 135840

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00426

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00443 AC: 6469 AN: 1461078 Hom.: 19 Cov.: 30 AF XY: 0.00428 AC XY: 3113 AN XY: 726882

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000278

Gnomad4 FIN exome AF: 0.00163

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.00298 AC: 453 AN: 152188 Hom.: 1 Cov.: 32 AF XY: 0.00296 AC XY: 220 AN XY: 74396

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00274

Gnomad4 NFE AF: 0.00462

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00361 Hom.: 1

Bravo AF: 0.00306

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00468

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NRP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 05, 2019

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

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.11
Dann	Benign	0.62

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: rs143858258; hg19: chr10-33474638; COSMIC: COSV55179123; COSMIC: COSV55179123;