10-33180348-C-T

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.2500G>A(p.Glu834Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00118 in 1,599,308 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E834D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (2 hom.)
• Consequence: NRP1 NM_003873.7 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.697

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 (MetaRNN=0.0074697435).
• BP6: Variant 10-33180348-C-T is Benign according to our data. Variant chr10-33180348-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 726098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 118 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRP1	NM_003873.7	c.2500G>A	p.Glu834Lys	missense_variant	17/17	ENST00000374867.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRP1	ENST00000374867.7	c.2500G>A	p.Glu834Lys	missense_variant	17/17	1	NM_003873.7	P3

Frequencies

GnomAD3 genomes AF: 0.000776 AC: 118 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000833 AC: 205 AN: 246188 Hom.: 0 AF XY: 0.000925 AC XY: 123 AN XY: 132958

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000382

Gnomad ASJ exome AF: 0.00274

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000338

Gnomad FIN exome AF: 0.000233

Gnomad NFE exome AF: 0.00138

Gnomad OTH exome AF: 0.000501

GnomAD4 exome AF: 0.00123 AC: 1776 AN: 1447150 Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 868 AN XY: 716978

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000385

Gnomad4 ASJ exome AF: 0.00316

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.000413

Gnomad4 NFE exome AF: 0.00144

Gnomad4 OTH exome AF: 0.000889

GnomAD4 genome AF: 0.000776 AC: 118 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.000780 AC XY: 58 AN XY: 74336

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000797

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.000832 AC: 101

EpiCase AF: 0.000874

EpiControl AF: 0.00161

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	NRP1: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Aug 22, 2018	- -

NRP1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 08, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	7.6
Dann	Benign	0.81
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.69	T;.;T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Benign	0.0075	T;T;T;T;T
MetaSVM	Benign	-0.52	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.090	N;N;N;N;N
REVEL	Benign	0.070
Sift	Benign	0.36	T;T;T;T;T
Sift4G	Benign	0.64	T;T;T;T;T
Polyphen		0.32	B;B;B;B;.
Vest4		0.12
MVP		0.66
MPC		0.27
ClinPred		0.0025	T
GERP RS		1.8
Varity_R		0.10
gMVP		0.54

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: rs150351789; hg19: chr10-33469276; COSMIC: COSV55170114;