rs1048804

Variant names:

• chr10-33180253-A-G
• rs1048804
• NM_003873.7:c.2595T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_003873.7(NRP1):​c.2595T>C​(p.Ser865Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,613,702 control chromosomes in the GnomAD database, including 65,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.33 (9940 hom., cov: 31)
  • Exomes 𝑓: 0.26 (55272 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.297
• Publications: 25 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 10-33180253-A-G is Benign according to our data. Variant chr10-33180253-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059358.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=-0.297 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.618 is higher than 0.05.

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.2595T>C	p.Ser865Ser	synonymous	Exon 17 of 17	NP_003864.5
	NRP1	NM_001244972.2		c.2577T>C	p.Ser859Ser	synonymous	Exon 17 of 17	NP_001231901.2
	NRP1	NM_001244973.2		c.2574T>C	p.Ser858Ser	synonymous	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.2595T>C	p.Ser865Ser	synonymous	Exon 17 of 17	ENSP00000364001.2	O14786-1
	NRP1	ENST00000395995.5	TSL:1	c.2544T>C	p.Ser848Ser	synonymous	Exon 16 of 16	ENSP00000379317.1	E9PEP6
	NRP1	ENST00000374875.5	TSL:1	c.2031T>C	p.Ser677Ser	synonymous	Exon 16 of 16	ENSP00000364009.1	Q5JWQ6

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50432 AN: 151794 Hom.: 9929 Cov.: 31

Gnomad AFR AF: 0.526

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.217

Gnomad ASJ AF: 0.251

Gnomad EAS AF: 0.636

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.334

GnomAD2 exomes AF: 0.285 AC: 71772 AN: 251420 AF XY: 0.287

Gnomad AFR exome AF: 0.531

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.266

Gnomad EAS exome AF: 0.641

Gnomad FIN exome AF: 0.185

Gnomad NFE exome AF: 0.242

Gnomad OTH exome AF: 0.274

GnomAD4 exome AF: 0.259 AC: 377979 AN: 1461790 Hom.: 55272 Cov.: 35 AF XY: 0.262 AC XY: 190227 AN XY: 727206

African (AFR) AF: 0.544 AC: 18208 AN: 33480

American (AMR) AF: 0.150 AC: 6691 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 6881 AN: 26134

East Asian (EAS) AF: 0.656 AC: 26035 AN: 39700

South Asian (SAS) AF: 0.351 AC: 30262 AN: 86252

European-Finnish (FIN) AF: 0.179 AC: 9575 AN: 53420

Middle Eastern (MID) AF: 0.329 AC: 1895 AN: 5766

European-Non Finnish (NFE) AF: 0.235 AC: 261127 AN: 1111924

Other (OTH) AF: 0.287 AC: 17305 AN: 60392

GnomAD4 genome AF: 0.332 AC: 50478 AN: 151912 Hom.: 9940 Cov.: 31 AF XY: 0.329 AC XY: 24434 AN XY: 74252

African (AFR) AF: 0.526 AC: 21748 AN: 41378

American (AMR) AF: 0.217 AC: 3307 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.251 AC: 872 AN: 3468

East Asian (EAS) AF: 0.636 AC: 3276 AN: 5148

South Asian (SAS) AF: 0.358 AC: 1718 AN: 4804

European-Finnish (FIN) AF: 0.196 AC: 2068 AN: 10576

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16469 AN: 67968

Other (OTH) AF: 0.335 AC: 706 AN: 2110

Alfa AF: 0.281 Hom.: 3100

Bravo AF: 0.345

Asia WGS AF: 0.488 AC: 1692 AN: 3478

EpiCase AF: 0.244

EpiControl AF: 0.246

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	NRP1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.4
DANN	Benign	0.55
PhyloP100		-0.30
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs1048804; hg19: chr10-33469181; COSMIC: COSV55162454;