rs12573218

Variant names:

• chr10-33298805-C-T
• rs12573218
• NM_003873.7:c.249-27949G>A

Variant summary

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

The NM_003873.7(NRP1):​c.249-27949G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,146 control chromosomes in the GnomAD database, including 1,049 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 0.11 (1049 hom., cov: 32)
• Consequence: NRP1 NM_003873.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.233
• Publications: 2 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=-0.81).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.136 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NRP1	NM_003873.7	c.249-27949G>A		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.249-27949G>A		intron_variant	Intron 2 of 16	1	NM_003873.7	ENSP00000364001.2

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16136 AN: 152028 Hom.: 1051 Cov.: 32

Gnomad AFR AF: 0.0348

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.248

Gnomad EAS AF: 0.113

Gnomad SAS AF: 0.108

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.138

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.106 AC: 16125 AN: 152146 Hom.: 1049 Cov.: 32 AF XY: 0.106 AC XY: 7913 AN XY: 74374

African (AFR) AF: 0.0348 AC: 1443 AN: 41522

American (AMR) AF: 0.109 AC: 1666 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 859 AN: 3470

East Asian (EAS) AF: 0.112 AC: 577 AN: 5160

South Asian (SAS) AF: 0.107 AC: 515 AN: 4816

European-Finnish (FIN) AF: 0.123 AC: 1303 AN: 10592

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.138 AC: 9387 AN: 67992

Other (OTH) AF: 0.105 AC: 223 AN: 2114

Alfa AF: 0.125 Hom.: 714

Bravo AF: 0.103

Asia WGS AF: 0.119 AC: 414 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.4
DANN	Benign	0.75
PhyloP100		-0.23
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: rs12573218; hg19: chr10-33587733;