10-33186354-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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 -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRP1	NM_003873.7	c.2197G>A	p.Val733Ile	missense_variant	Exon 14 of 17	ENST00000374867.7	NP_003864.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRP1	ENST00000374867.7	c.2197G>A	p.Val733Ile	missense_variant	Exon 14 of 17	1	NM_003873.7	ENSP00000364001.2
NRP1	ENST00000395995.5	c.2197G>A	p.Val733Ile	missense_variant	Exon 14 of 16	1		ENSP00000379317.1
NRP1	ENST00000374875.5	c.1633G>A	p.Val545Ile	missense_variant	Exon 13 of 16	1		ENSP00000364009.1
NRP1	ENST00000265371.8	c.2197G>A	p.Val733Ile	missense_variant	Exon 15 of 18	5		ENSP00000265371.3

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

GnomAD3 exomes AF: 0.124 AC: 31055 AN: 251220 Hom.: 2431 AF XY: 0.118 AC XY: 16027 AN XY: 135762

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 SAS exome AF: 0.0964

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

Gnomad4 AFR exome AF: 0.0160

Gnomad4 AMR exome AF: 0.243

Gnomad4 ASJ exome AF: 0.107

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.0961

Gnomad4 FIN exome AF: 0.160

Gnomad4 NFE exome AF: 0.0981

Gnomad4 OTH exome AF: 0.101

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

Gnomad4 AFR AF: 0.0215

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.116

Gnomad4 EAS AF: 0.132

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.103

Gnomad4 OTH AF: 0.100

Alfa AF: 0.0994 Hom.: 1980

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

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
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;T;T
Eigen	Benign	0.014
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.94	D;.;D;D
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.24	.;N;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.47	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.76	T;T;T;T
Polyphen		0.36	B;B;B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228638; hg19: chr10-33475282; COSMIC: COSV55161446; COSMIC: COSV55161446;