Genetic Variant NM_017514.5:c.40G>A (chrX-154460223-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_017514.5(PLXNA3):c.40G>A(p.Val14Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,207,400 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000082 ( 0 hom. 5 hem. )

Consequence

PLXNA3
NM_017514.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.76

Variant links:

Genes affected

PLXNA3 (HGNC:9101): (plexin A3) This gene encodes a member of the plexin class of proteins. The encoded protein is a class 3 semaphorin receptor, and may be involved in cytoskeletal remodeling and as well as apoptosis. Studies of a similar gene in zebrafish suggest that it is important for axon pathfinding in the developing nervous system. This gene may be associated with tumor progression. [provided by RefSeq, Aug 2013]

PLXNA3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05110833).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA3	NM_017514.5 link	c.40G>A	p.Val14Met	missense_variant	Exon 2 of 33	ENST00000369682.4	NP_059984.3	P51805
PLXNA3	XM_047442247.1 link	c.40G>A	p.Val14Met	missense_variant	Exon 2 of 22		XP_047298203.1
PLXNA3	XR_007068193.1 link	n.215G>A		non_coding_transcript_exon_variant	Exon 2 of 32
PLXNA3	XR_430556.4 link	n.215G>A		non_coding_transcript_exon_variant	Exon 2 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLXNA3	ENST00000369682.4 link	c.40G>A	p.Val14Met	missense_variant	Exon 2 of 33	1	NM_017514.5	ENSP00000358696.3		P51805
PLXNA3	ENST00000495040.1 link	n.146-876G>A		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes

AF:

0.00000889

AC:

AN:

112475

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34639

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:

0.000280

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

178600

Hom.:

AF XY:

0.0000307

AC XY:

AN XY:

65194

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000219

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1094873

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

361057

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000833

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000889

AC:

AN:

112527

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34701

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000281

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.40G>A (p.V14M) alteration is located in exon 2 (coding exon 1) of the PLXNA3 gene. This alteration results from a G to A substitution at nucleotide position 40, causing the valine (V) at amino acid position 14 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.99

CADD

Benign

0.071

DANN

Benign

0.91

FATHMM_MKL

Benign

0.058

M_CAP

Benign

0.0057

MetaRNN

Benign

0.051

MetaSVM

Benign

-0.92

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.11

REVEL

Benign

0.012

Sift

Benign

0.13

Sift4G

Benign

0.24

Vest4

0.11

MutPred

0.49

Loss of catalytic residue at V14 (P = 0.0236);

MVP

0.14

ClinPred

0.13

GERP RS

-3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.36

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

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