rs2229935

Variant names:

• chr10-33221735-G-A
• rs2229935
• NM_003873.7:c.1266C>T

Your query was ambiguous. Multiple possible variants found:

• chr10-33221735-G-A
• chr10-33221735-G-C
• chr10-33221735-G-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003873.7(NRP1):​c.1266C>T​(p.Tyr422Tyr) 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 (no stars).

• Frequency:
  • Genomes: 𝑓 0.28 (6438 hom., cov: 32)
  • Exomes 𝑓: 0.28 (61456 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.379
• Publications: 21 publications found

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]

NRP1 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 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 VariationId is 3060922.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
NRP1	NM_003873.7	c.1266C>T	p.Tyr422Tyr	synonymous_variant	Exon 8 of 17	ENST00000374867.7	NP_003864.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRP1	ENST00000374867.7	c.1266C>T	p.Tyr422Tyr	synonymous_variant	Exon 8 of 17	1	NM_003873.7	ENSP00000364001.2

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

GnomAD2 exomes AF: 0.322 AC: 81001 AN: 251332 AF XY: 0.316

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 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

African (AFR) AF: 0.206 AC: 6897 AN: 33442

American (AMR) AF: 0.419 AC: 18748 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 7523 AN: 26106

East Asian (EAS) AF: 0.626 AC: 24814 AN: 39662

South Asian (SAS) AF: 0.339 AC: 29191 AN: 86192

European-Finnish (FIN) AF: 0.274 AC: 14619 AN: 53398

Middle Eastern (MID) AF: 0.219 AC: 1264 AN: 5762

European-Non Finnish (NFE) AF: 0.260 AC: 288993 AN: 1109672

Other (OTH) AF: 0.288 AC: 17388 AN: 60288

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

African (AFR) AF: 0.209 AC: 8668 AN: 41460

American (AMR) AF: 0.374 AC: 5711 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1017 AN: 3470

East Asian (EAS) AF: 0.620 AC: 3202 AN: 5164

South Asian (SAS) AF: 0.348 AC: 1677 AN: 4818

European-Finnish (FIN) AF: 0.290 AC: 3055 AN: 10548

Middle Eastern (MID) AF: 0.185 AC: 54 AN: 292

European-Non Finnish (NFE) AF: 0.270 AC: 18384 AN: 67992

Other (OTH) AF: 0.296 AC: 624 AN: 2110

Alfa AF: 0.276 Hom.: 11826

Bravo AF: 0.287

Asia WGS AF: 0.460 AC: 1598 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NRP1-related disorder Benign:1

Aug 01, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.38
Mutation Taster		=83/17	polymorphism (auto)

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

Other links and lift over

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