Genetic Variant NRP1:p.Val877Ile (chr10-33180219-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003873.7(NRP1):c.2629G>A(p.Val877Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V877F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

NRP1
NM_003873.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.57

Publications

1 publications found

Variant links:

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

NRP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NRP1	NM_003873.7	MANE Select	c.2629G>A	p.Val877Ile	missense	Exon 17 of 17	NP_003864.5
NRP1	NM_001244972.2		c.2611G>A	p.Val871Ile	missense	Exon 17 of 17	NP_001231901.2
NRP1	NM_001244973.2		c.2608G>A	p.Val870Ile	missense	Exon 17 of 17	NP_001231902.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NRP1	ENST00000374867.7	TSL:1 MANE Select	c.2629G>A	p.Val877Ile	missense	Exon 17 of 17	ENSP00000364001.2	O14786-1
NRP1	ENST00000395995.5	TSL:1	c.2578G>A	p.Val860Ile	missense	Exon 16 of 16	ENSP00000379317.1	E9PEP6
NRP1	ENST00000374875.5	TSL:1	c.2065G>A	p.Val689Ile	missense	Exon 16 of 16	ENSP00000364009.1	Q5JWQ6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.66

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.090

MetaRNN

Uncertain

0.48

MetaSVM

Pathogenic

0.83

MutationAssessor

Benign

1.4

PhyloP100

7.6

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

0.010

REVEL

Uncertain

0.43

Sift

Uncertain

0.012

Sift4G

Uncertain

0.043

Polyphen

1.0

Vest4

0.52

MutPred

0.33

Loss of catalytic residue at V877 (P = 0.0057)

MVP

0.60

MPC

0.79

ClinPred

0.74

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.14

gMVP

0.51

Mutation Taster

=60/40

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over