10-33180358-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003873.7(NRP1):c.2490G>A(p.Thr830=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0186 in 1,589,592 control chromosomes in the GnomAD database, including 335 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (19 hom., cov: 32)
  • Exomes 𝑓: 0.019 (316 hom.)
• Consequence: NRP1 NM_003873.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.19

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 10-33180358-C-T is Benign according to our data. Variant chr10-33180358-C-T is described in ClinVar as [Benign]. Clinvar id is 3038237.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0131 (1999/152254) while in subpopulation NFE AF= 0.0227 (1543/68032). AF 95% confidence interval is 0.0217. There are 19 homozygotes in gnomad4. There are 906 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2000 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.2490G>A	p.Thr830=	synonymous_variant	17/17	ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.2490G>A	p.Thr830=	synonymous_variant	17/17	1	NM_003873.7	P3

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 2000 AN: 152136 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00679

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0227

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.0141 AC: 3389 AN: 240782 Hom.: 48 AF XY: 0.0146 AC XY: 1900 AN XY: 130042

Gnomad AFR exome AF: 0.00336

Gnomad AMR exome AF: 0.00702

Gnomad ASJ exome AF: 0.00894

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00515

Gnomad FIN exome AF: 0.00647

Gnomad NFE exome AF: 0.0242

Gnomad OTH exome AF: 0.0155

GnomAD4 exome AF: 0.0192 AC: 27560 AN: 1437338 Hom.: 316 Cov.: 32 AF XY: 0.0189 AC XY: 13422 AN XY: 710892

Gnomad4 AFR exome AF: 0.00306

Gnomad4 AMR exome AF: 0.00742

Gnomad4 ASJ exome AF: 0.0105

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00578

Gnomad4 FIN exome AF: 0.00728

Gnomad4 NFE exome AF: 0.0229

Gnomad4 OTH exome AF: 0.0151

GnomAD4 genome AF: 0.0131 AC: 1999 AN: 152254 Hom.: 19 Cov.: 32 AF XY: 0.0122 AC XY: 906 AN XY: 74436

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.00883

Gnomad4 ASJ AF: 0.00979

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00679

Gnomad4 NFE AF: 0.0227

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.0143 Hom.: 9

Bravo AF: 0.0127

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NRP1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
Cadd	Benign	1.4
Dann	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs2229936; hg19: chr10-33469286;