10-33180368-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003873.7(NRP1):c.2483-3T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,575,732 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: NRP1 NM_003873.7 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002190
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.488

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 10-33180368-A-G is Benign according to our data. Variant chr10-33180368-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 770962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 162 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.2483-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.2483-3T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003873.7	P3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 162 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00499

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00130 AC: 295 AN: 227678 Hom.: 0 AF XY: 0.00121 AC XY: 149 AN XY: 122808

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.0000333

Gnomad ASJ exome AF: 0.00128

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00629

Gnomad NFE exome AF: 0.00141

Gnomad OTH exome AF: 0.00110

GnomAD4 exome AF: 0.00136 AC: 1935 AN: 1423486 Hom.: 2 Cov.: 31 AF XY: 0.00133 AC XY: 934 AN XY: 702690

Gnomad4 AFR exome AF: 0.000344

Gnomad4 AMR exome AF: 0.0000996

Gnomad4 ASJ exome AF: 0.00120

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00559

Gnomad4 NFE exome AF: 0.00141

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.00106 AC: 162 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74450

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00499

Gnomad4 NFE AF: 0.00140

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.000627

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NRP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 19, 2021

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

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.17
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0060
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: rs199689769; hg19: chr10-33469296;