NM_003873.7:c.248+25634A>G

Variant names:

• chr10-33305074-T-C
• rs2065364
• NM_003873.7:c.248+25634A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003873.7(NRP1):​c.248+25634A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.709 in 152,160 control chromosomes in the GnomAD database, including 38,466 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.71 (38466 hom., cov: 33)
• Consequence: NRP1 NM_003873.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.44
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRP1	NM_003873.7	c.248+25634A>G		intron_variant	Intron 2 of 16	ENST00000374867.7	NP_003864.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NRP1	ENST00000374867.7	c.248+25634A>G		intron_variant	Intron 2 of 16	1	NM_003873.7	ENSP00000364001.2

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107726 AN: 152042 Hom.: 38429 Cov.: 33

Gnomad AFR AF: 0.652

Gnomad AMI AF: 0.617

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.729

Gnomad EAS AF: 0.686

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.782

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.725

Gnomad OTH AF: 0.708

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.709 AC: 107818 AN: 152160 Hom.: 38466 Cov.: 33 AF XY: 0.711 AC XY: 52884 AN XY: 74382

African (AFR) AF: 0.653 AC: 27088 AN: 41494

American (AMR) AF: 0.760 AC: 11622 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.729 AC: 2530 AN: 3472

East Asian (EAS) AF: 0.687 AC: 3552 AN: 5174

South Asian (SAS) AF: 0.657 AC: 3167 AN: 4820

European-Finnish (FIN) AF: 0.782 AC: 8283 AN: 10586

Middle Eastern (MID) AF: 0.718 AC: 211 AN: 294

European-Non Finnish (NFE) AF: 0.725 AC: 49304 AN: 68006

Other (OTH) AF: 0.709 AC: 1498 AN: 2114

Alfa AF: 0.718 Hom.: 62232

Bravo AF: 0.707

Asia WGS AF: 0.655 AC: 2282 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.12
DANN	Benign	0.55
PhyloP100		-2.4
Mutation Taster		=100/0	polymorphism (auto)

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: rs2065364; hg19: chr10-33594002;