NM_003873.7:c.2197G>A

Variant names:

• chr10-33186354-C-T
• rs2228638
• NM_003873.7:c.2197G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003873.7(NRP1):​c.2197G>A​(p.Val733Ile) variant causes a missense change. The variant allele was found at a frequency of 0.103 in 1,613,934 control chromosomes in the GnomAD database, including 9,805 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.096 (927 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8878 hom.)
• Consequence: NRP1 NM_003873.7 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.35
• Publications: 49 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024904907).
• BP6: Variant 10-33186354-C-T is Benign according to our data. Variant chr10-33186354-C-T is described in ClinVar as Benign. ClinVar VariationId is 3055728.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.188 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.2197G>A	p.Val733Ile	missense	Exon 14 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.2179G>A	p.Val727Ile	missense	Exon 14 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.2176G>A	p.Val726Ile	missense	Exon 14 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.2197G>A	p.Val733Ile	missense	Exon 14 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.2197G>A	p.Val733Ile	missense	Exon 14 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374875.5	TSL:1	c.1633G>A	p.Val545Ile	missense	Exon 13 of 16	ENSP00000364009.1	Q5JWQ6

Frequencies

GnomAD3 genomes AF: 0.0958 AC: 14559 AN: 151960 Hom.: 929 Cov.: 32

Gnomad AFR AF: 0.0216

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.132

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.102

GnomAD2 exomes AF: 0.124 AC: 31055 AN: 251220 AF XY: 0.118

Gnomad AFR exome AF: 0.0205

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.128

Gnomad FIN exome AF: 0.157

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.104 AC: 151633 AN: 1461854 Hom.: 8878 Cov.: 32 AF XY: 0.103 AC XY: 74874 AN XY: 727226

African (AFR) AF: 0.0160 AC: 536 AN: 33480

American (AMR) AF: 0.243 AC: 10850 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 2800 AN: 26136

East Asian (EAS) AF: 0.128 AC: 5083 AN: 39694

South Asian (SAS) AF: 0.0961 AC: 8292 AN: 86252

European-Finnish (FIN) AF: 0.160 AC: 8572 AN: 53416

Middle Eastern (MID) AF: 0.0532 AC: 307 AN: 5768

European-Non Finnish (NFE) AF: 0.0981 AC: 109079 AN: 1111998

Other (OTH) AF: 0.101 AC: 6114 AN: 60396

GnomAD4 genome AF: 0.0957 AC: 14557 AN: 152080 Hom.: 927 Cov.: 32 AF XY: 0.100 AC XY: 7446 AN XY: 74300

African (AFR) AF: 0.0215 AC: 892 AN: 41504

American (AMR) AF: 0.194 AC: 2961 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 403 AN: 3466

East Asian (EAS) AF: 0.132 AC: 679 AN: 5162

South Asian (SAS) AF: 0.105 AC: 504 AN: 4818

European-Finnish (FIN) AF: 0.166 AC: 1755 AN: 10554

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.103 AC: 7034 AN: 67986

Other (OTH) AF: 0.100 AC: 212 AN: 2110

Alfa AF: 0.0981 Hom.: 2730

Bravo AF: 0.0957

TwinsUK AF: 0.0998 AC: 370

ALSPAC AF: 0.0931 AC: 359

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.107 AC: 918

ExAC AF: 0.116 AC: 14046

Asia WGS AF: 0.115 AC: 402 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
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	20
DANN	Benign	0.29
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.014
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.24	N
PhyloP100		4.3
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.18
Sift	Benign	0.20	T
Sift4G	Benign	0.76	T
Polyphen		0.36	B
Vest4		0.074
MPC		0.22
ClinPred		0.015	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.27
gMVP		0.24
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2228638; hg19: chr10-33475282; COSMIC: COSV55161446; COSMIC: COSV55161446;