rs2229935

chr10-33221735-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003873.7(NRP1):c.1266C>T(p.Tyr422=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.281 in 1,611,294 control chromosomes in the GnomAD database, including 67,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6438 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61456 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.379

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 10-33221735-G-A is Benign according to our data. Variant chr10-33221735-G-A is described in ClinVar as [Benign]. Clinvar id is 3060922.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.379 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.1266C>T	p.Tyr422=	synonymous_variant	8/17	ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.1266C>T	p.Tyr422=	synonymous_variant	8/17	1	NM_003873.7	P3

Frequencies

GnomAD3 genomes AF: 0.280 AC: 42596 AN: 151930 Hom.: 6437 Cov.: 32

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.373

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.621

Gnomad SAS AF: 0.349

Gnomad FIN AF: 0.290

Gnomad MID AF: 0.182

Gnomad NFE AF: 0.270

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.322 AC: 81001 AN: 251332 Hom.: 14676 AF XY: 0.316 AC XY: 42950 AN XY: 135848

Gnomad AFR exome AF: 0.213

Gnomad AMR exome AF: 0.426

Gnomad ASJ exome AF: 0.290

Gnomad EAS exome AF: 0.639

Gnomad SAS exome AF: 0.338

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.265

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.281 AC: 409437 AN: 1459244 Hom.: 61456 Cov.: 33 AF XY: 0.282 AC XY: 204539 AN XY: 725966

Gnomad4 AFR exome AF: 0.206

Gnomad4 AMR exome AF: 0.419

Gnomad4 ASJ exome AF: 0.288

Gnomad4 EAS exome AF: 0.626

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.274

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.288

GnomAD4 genome AF: 0.280 AC: 42609 AN: 152050 Hom.: 6438 Cov.: 32 AF XY: 0.284 AC XY: 21120 AN XY: 74300

Gnomad4 AFR AF: 0.209

Gnomad4 AMR AF: 0.374

Gnomad4 ASJ AF: 0.293

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.348

Gnomad4 FIN AF: 0.290

Gnomad4 NFE AF: 0.270

Gnomad4 OTH AF: 0.296

Alfa AF: 0.266 Hom.: 3508

Bravo AF: 0.287

Asia WGS AF: 0.460 AC: 1598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRP1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2022

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	-0.47
Cadd	Benign	6.3
Dann	Benign	0.45

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: rs2229935; hg19: chr10-33510663; COSMIC: COSV55167102;