X-154460238-G-A

Position:

chrX-154460238-G-A

Variant summary

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

The NM_017514.5(PLXNA3):c.55G>A(p.Gly19Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,208,510 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 50 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.00015 ( 0 hom. 50 hem. )

Consequence

PLXNA3
NM_017514.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 1.18

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:

PLXNA3 (HGNC:):

PLXNA3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05299416).

BS2

High Hemizygotes in GnomAdExome4 at 50 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXNA3	NM_017514.5 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	2/33	ENST00000369682.4	NP_059984.3	P51805
PLXNA3	XM_047442247.1 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	2/22		XP_047298203.1
PLXNA3	XR_007068193.1 linkuse as main transcript	n.230G>A		non_coding_transcript_exon_variant	2/32
PLXNA3	XR_430556.4 linkuse as main transcript	n.230G>A		non_coding_transcript_exon_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLXNA3	ENST00000369682.4 linkuse as main transcript	c.55G>A	p.Gly19Ser	missense_variant	2/33	1	NM_017514.5	ENSP00000358696.3		P51805
PLXNA3	ENST00000495040.1 linkuse as main transcript	n.146-861G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000801

AC:

AN:

112420

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34586

show subpopulations

Gnomad AFR

AF:

0.0000647

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000929

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:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000778

AC:

AN:

179866

Hom.:

AF XY:

0.0000152

AC XY:

AN XY:

65880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000733

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000153

AC:

168

AN:

1096036

Hom.:

Cov.:

AF XY:

0.000138

AC XY:

AN XY:

362078

show subpopulations

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000193

Gnomad4 OTH exome

AF:

0.000109

GnomAD4 genome

AF:

0.0000800

AC:

AN:

112474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34650

show subpopulations

Gnomad4 AFR

AF:

0.0000645

Gnomad4 AMR

AF:

0.0000928

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.55G>A (p.G19S) 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 55, causing the glycine (G) at amino acid position 19 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PLXNA3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 03, 2024

The PLXNA3 c.55G>A variant is predicted to result in the amino acid substitution p.Gly19Ser. To our knowledge, this variant has not been reported in the literature. The c.55G>A variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including one hemizygote, in gnomAD v2 (as displayed in the table above). However, in gnomAD v4.1 (available only on GRCh38), while it occurs at a similar allele frequency of 0.019% in the same population, the whole dataset includes 50 hemizygotes for this variant. This data is not consistent with this variant being a primary cause of disease. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Uncertain

0.97

FATHMM_MKL

Benign

0.66

M_CAP

Benign

0.023

MetaRNN

Benign

0.053

MetaSVM

Benign

-0.94

PrimateAI

Benign

0.42

PROVEAN

Benign

-0.16

REVEL

Benign

0.17

Sift

Benign

0.57

Sift4G

Benign

0.93

Vest4

0.18

MVP

0.56

ClinPred

0.019

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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