X-154460239-G-A

Position:

chrX-154460239-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_017514.5(PLXNA3):c.56G>A(p.Gly19Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000333 in 1,208,325 control chromosomes in the GnomAD database, including 1 homozygotes. There are 120 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00061 ( 1 hom., 14 hem., cov: 25)

Exomes 𝑓: 0.00030 ( 0 hom. 106 hem. )

Consequence

PLXNA3
NM_017514.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 0.471

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049319565).

BP6

Variant X-154460239-G-A is Benign according to our data. Variant chrX-154460239-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 599563.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}. Variant chrX-154460239-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXNA3	NM_017514.5 linkuse as main transcript	c.56G>A	p.Gly19Asp	missense_variant	2/33	ENST00000369682.4	NP_059984.3	P51805
PLXNA3	XM_047442247.1 linkuse as main transcript	c.56G>A	p.Gly19Asp	missense_variant	2/22		XP_047298203.1
PLXNA3	XR_007068193.1 linkuse as main transcript	n.231G>A		non_coding_transcript_exon_variant	2/32
PLXNA3	XR_430556.4 linkuse as main transcript	n.231G>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.56G>A	p.Gly19Asp	missense_variant	2/33	1	NM_017514.5	ENSP00000358696.3		P51805
PLXNA3	ENST00000495040.1 linkuse as main transcript	n.146-860G>A		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

112370

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

AN XY:

34544

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0666

Gnomad AMR

AF:

0.0000930

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:

0.000414

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000217

AC:

AN:

179845

Hom.:

AF XY:

0.000213

AC XY:

AN XY:

65877

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000293

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:

0.000391

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000305

AC:

334

AN:

1095955

Hom.:

Cov.:

AF XY:

0.000293

AC XY:

106

AN XY:

362005

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000199

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:

0.000371

Gnomad4 OTH exome

AF:

0.000326

GnomAD4 genome

AF:

0.000605

AC:

AN:

112370

Hom.:

Cov.:

AF XY:

0.000405

AC XY:

AN XY:

34544

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000930

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000414

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000408

Hom.:

Bravo

AF:

0.000846

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000297

AC:

ExAC

AF:

0.000214

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 02, 2024	The c.56G>A (p.G19D) 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 56, causing the glycine (G) at amino acid position 19 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Short stature

Pathogenic:1

Likely pathogenic, no assertion criteria provided

case-control

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Nov 18, 2001

- -

PLXNA3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 10, 2024

The PLXNA3 c.56G>A variant is predicted to result in the amino acid substitution p.Gly19Asp. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.039% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including 16 hemizygous individuals. Although we suspect this variant may be benign, 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

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.63

CADD

Benign

DANN

Uncertain

0.99

FATHMM_MKL

Benign

0.54

M_CAP

Benign

0.022

MetaRNN

Benign

0.0049

MetaSVM

Benign

-0.92

PrimateAI

Uncertain

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.14

Sift

Uncertain

0.015

Sift4G

Benign

0.14

Vest4

0.29

MVP

0.52

ClinPred

0.030

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.49

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