chr10-33180326-T-C

Variant names:

• chr10-33180326-T-C
• NM_003873.7:c.2522A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003873.7(NRP1):​c.2522A>G​(p.Lys841Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRP1 NM_003873.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.86
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13212606).

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.2522A>G	p.Lys841Arg	missense	Exon 17 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.2504A>G	p.Lys835Arg	missense	Exon 17 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.2501A>G	p.Lys834Arg	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.2522A>G	p.Lys841Arg	missense	Exon 17 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.2471A>G	p.Lys824Arg	missense	Exon 16 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374875.5	TSL:1	c.1958A>G	p.Lys653Arg	missense	Exon 16 of 16	ENSP00000364009.1	Q5JWQ6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.054	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.9
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.21
Sift	Benign	0.51	T
Sift4G	Benign	0.51	T
Polyphen		0.0	B
Vest4		0.025
MutPred		0.32		Loss of ubiquitination at K841 (P = 0.0059)
MVP		0.50
MPC		0.20
ClinPred		0.32	T
GERP RS		3.6
Varity_R		0.069
gMVP		0.35
Mutation Taster		=92/8	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

hg19: chr10-33469254;