1-208028046-T-C

Position:

chr1-208028046-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_025179.4(PLXNA2):c.5552A>G(p.Asn1851Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000553 in 1,608,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

PLXNA2
NM_025179.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 4.01

Variant links:

Genes affected

PLXNA2 (HGNC:9100): (plexin A2) This gene encodes a member of the plexin-A family of semaphorin co-receptors. Semaphorins are a large family of secreted or membrane-bound proteins that mediate repulsive effects on axon pathfinding during nervous system development. A subset of semaphorins are recognized by plexin-A/neuropilin transmembrane receptor complexes, triggering a cellular signal transduction cascade that leads to axon repulsion. This plexin-A family member is thought to transduce signals from semaphorin-3A and -3C. [provided by RefSeq, Jul 2008]

PLXNA2 links:

PLXNA2 (HGNC:):

PLXNA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15440306).

BS2

High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXNA2	NM_025179.4 linkuse as main transcript	c.5552A>G	p.Asn1851Ser	missense_variant	31/32	ENST00000367033.4	NP_079455.3	O75051-1
PLXNA2	XM_005273164.4 linkuse as main transcript	c.5792A>G	p.Asn1931Ser	missense_variant	32/33		XP_005273221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLXNA2	ENST00000367033.4 linkuse as main transcript	c.5552A>G	p.Asn1851Ser	missense_variant	31/32	1	NM_025179.4	ENSP00000356000.3		O75051-1
PLXNA2	ENST00000483048.1 linkuse as main transcript	n.1588A>G		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes

AF:

0.0000923

AC:

AN:

151712

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000192

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000402

AC:

AN:

248676

Hom.:

AF XY:

0.0000446

AC XY:

AN XY:

134414

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000515

AC:

AN:

1457064

Hom.:

Cov.:

AF XY:

0.0000483

AC XY:

AN XY:

724786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000192

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000234

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000559

Gnomad4 OTH exome

AF:

0.0000831

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151712

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74104

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000192

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.000249

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000549

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PLXNA2 protein function. This variant has not been reported in the literature in individuals affected with PLXNA2-related conditions. This variant is present in population databases (rs141837222, gnomAD 0.01%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1851 of the PLXNA2 protein (p.Asn1851Ser). -

PLXNA2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 17, 2024

The PLXNA2 c.5552A>G variant is predicted to result in the amino acid substitution p.Asn1851Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.90

DEOGEN2

Benign

0.076

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.0045

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.68

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.66

REVEL

Benign

0.069

Sift

Benign

0.95

Sift4G

Benign

0.60

Polyphen

0.0090

Vest4

0.26

MVP

0.44

MPC

0.47

ClinPred

0.091

GERP RS

4.4

Varity_R

0.076

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over