10-33186354-C-G

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003873.7(NRP1):​c.2197G>C​(p.Val733Leu) variant causes a missense change. 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. V733I) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NRP1 NM_003873.7 missense
• Clinical Significance: Not reported in ClinVar
• 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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRP1	NM_003873.7	c.2197G>C	p.Val733Leu	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>C	p.Val733Leu	missense_variant	Exon 14 of 17	1	NM_003873.7	ENSP00000364001.2
NRP1	ENST00000395995.5	c.2197G>C	p.Val733Leu	missense_variant	Exon 14 of 16	1		ENSP00000379317.1
NRP1	ENST00000374875.5	c.1633G>C	p.Val545Leu	missense_variant	Exon 13 of 16	1		ENSP00000364009.1
NRP1	ENST00000265371.8	c.2197G>C	p.Val733Leu	missense_variant	Exon 15 of 18	5		ENSP00000265371.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.054	.;T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;.;D;D
M_CAP	Benign	0.0083	T
MetaRNN	Uncertain	0.63	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	.;L;.;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.62	N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.15	T;T;T;T
Sift4G	Benign	0.46	T;T;T;T
Polyphen		0.90	P;P;P;P
Vest4		0.46
MutPred		0.72		.;Loss of MoRF binding (P = 0.0922);Loss of MoRF binding (P = 0.0922);Loss of MoRF binding (P = 0.0922);
MVP		0.29
MPC		0.48
ClinPred		0.55	D
GERP RS		5.9
Varity_R		0.65
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-33475282;