10-33334323-G-A

Variant names:

• chr10-33334323-G-A
• rs3750733
• NM_003873.7:c.60C>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.60C>T​(p.Gly20Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0939 in 1,542,044 control chromosomes in the GnomAD database, including 7,778 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.080 (621 hom., cov: 31)
  • Exomes 𝑓: 0.095 (7157 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.58
• Publications: 10 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=-0.5).
• BP6: Variant 10-33334323-G-A is Benign according to our data. Variant chr10-33334323-G-A is described in ClinVar as Benign. ClinVar VariationId is 3057002.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.201 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003873.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRP1	NM_003873.7	MANE Select	c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 17	NP_001231902.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NRP1	ENST00000374867.7	TSL:1 MANE Select	c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374823.9	TSL:1	c.60C>T	p.Gly20Gly	synonymous	Exon 1 of 11	ENSP00000363956.5	Q5T7F0

Frequencies

GnomAD3 genomes AF: 0.0798 AC: 12145 AN: 152110 Hom.: 617 Cov.: 31

Gnomad AFR AF: 0.0478

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0900

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.0676

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0837

Gnomad OTH AF: 0.0808

GnomAD2 exomes AF: 0.109 AC: 15177 AN: 139364 AF XY: 0.112

Gnomad AFR exome AF: 0.0430

Gnomad AMR exome AF: 0.124

Gnomad ASJ exome AF: 0.0586

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.0632

Gnomad NFE exome AF: 0.0832

Gnomad OTH exome AF: 0.0927

GnomAD4 exome AF: 0.0955 AC: 132685 AN: 1389816 Hom.: 7157 Cov.: 31 AF XY: 0.0974 AC XY: 66788 AN XY: 685678

African (AFR) AF: 0.0430 AC: 1355 AN: 31508

American (AMR) AF: 0.116 AC: 4146 AN: 35672

Ashkenazi Jewish (ASJ) AF: 0.0554 AC: 1391 AN: 25128

East Asian (EAS) AF: 0.197 AC: 6989 AN: 35528

South Asian (SAS) AF: 0.170 AC: 13439 AN: 78988

European-Finnish (FIN) AF: 0.0668 AC: 2834 AN: 42414

Middle Eastern (MID) AF: 0.0642 AC: 311 AN: 4848

European-Non Finnish (NFE) AF: 0.0895 AC: 96437 AN: 1077932

Other (OTH) AF: 0.100 AC: 5783 AN: 57798

GnomAD4 genome AF: 0.0799 AC: 12159 AN: 152228 Hom.: 621 Cov.: 31 AF XY: 0.0819 AC XY: 6095 AN XY: 74430

African (AFR) AF: 0.0477 AC: 1984 AN: 41554

American (AMR) AF: 0.0907 AC: 1387 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3468

East Asian (EAS) AF: 0.211 AC: 1086 AN: 5136

South Asian (SAS) AF: 0.182 AC: 878 AN: 4826

European-Finnish (FIN) AF: 0.0676 AC: 717 AN: 10610

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0836 AC: 5689 AN: 68020

Other (OTH) AF: 0.0818 AC: 173 AN: 2114

Alfa AF: 0.0850 Hom.: 523

Bravo AF: 0.0778

Asia WGS AF: 0.214 AC: 745 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NRP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	14
DANN	Benign	0.97
PhyloP100		1.6
PromoterAI		-0.019	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=297/3	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: rs3750733; hg19: chr10-33623251; COSMIC: COSV55171325;