chr10-33180216-C-T

Variant names:

• chr10-33180216-C-T
• rs200330871
• NM_003873.7:c.2632G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_003873.7(NRP1):​c.2632G>A​(p.Val878Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000929 in 1,614,018 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000099 (1 hom.)
• Consequence: NRP1 NM_003873.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.76
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22154862).

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.2632G>A	p.Val878Met	missense	Exon 17 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.2614G>A	p.Val872Met	missense	Exon 17 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.2611G>A	p.Val871Met	missense	Exon 17 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.2632G>A	p.Val878Met	missense	Exon 17 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.2581G>A	p.Val861Met	missense	Exon 16 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374875.5	TSL:1	c.2068G>A	p.Val690Met	missense	Exon 16 of 16	ENSP00000364009.1	Q5JWQ6

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000954 AC: 24 AN: 251464 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000992 AC: 145 AN: 1461892 Hom.: 1 Cov.: 30 AF XY: 0.000111 AC XY: 81 AN XY: 727248

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000854 AC: 95 AN: 1112010

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74308

African (AFR) AF: 0.00 AC: 0 AN: 41408

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000706 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000115 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	NRP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.22	T
MetaSVM	Uncertain	0.76	D
MutationAssessor	Benign	1.4	L
PhyloP100		4.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.39
MutPred		0.28		Loss of sheet (P = 0.0126)
MVP		0.59
MPC		0.45
ClinPred		0.12	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.63
Mutation Taster		=88/12	polymorphism

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: rs200330871; hg19: chr10-33469144; COSMIC: COSV55176377;