X-154460262-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017514.5(PLXNA3):c.79G>A(p.Val27Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000669 in 1,208,166 control chromosomes in the GnomAD database, including 2 homozygotes. There are 255 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00061 (0 hom., 24 hem., cov: 24)
  • Exomes 𝑓: 0.00067 (2 hom. 231 hem.)
• Consequence: PLXNA3 NM_017514.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.302

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03151402).
• BP6: Variant X-154460262-G-A is Benign according to our data. Variant chrX-154460262-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2401729.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chrX-154460262-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXNA3	NM_017514.5	c.79G>A	p.Val27Met	missense_variant	2/33	ENST00000369682.4
PLXNA3	XM_047442247.1	c.79G>A	p.Val27Met	missense_variant	2/22
PLXNA3	XR_007068193.1	n.254G>A		non_coding_transcript_exon_variant	2/32
PLXNA3	XR_430556.4	n.254G>A		non_coding_transcript_exon_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXNA3	ENST00000369682.4	c.79G>A	p.Val27Met	missense_variant	2/33	1	NM_017514.5	P1
PLXNA3	ENST00000495040.1	n.146-837G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000606 AC: 68 AN: 112257 Hom.: 0 Cov.: 24 AF XY: 0.000668 AC XY: 23 AN XY: 34427

Gnomad AFR AF: 0.000356

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: 0.00107

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000410 AC: 74 AN: 180657 Hom.: 0 AF XY: 0.000483 AC XY: 32 AN XY: 66301

Gnomad AFR exome AF: 0.000460

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000633

Gnomad NFE exome AF: 0.000839

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000674 AC: 739 AN: 1095857 Hom.: 2 Cov.: 31 AF XY: 0.000639 AC XY: 231 AN XY: 361763

Gnomad4 AFR exome AF: 0.000266

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000555

Gnomad4 FIN exome AF: 0.0000251

Gnomad4 NFE exome AF: 0.000842

Gnomad4 OTH exome AF: 0.000435

GnomAD4 genome AF: 0.000614 AC: 69 AN: 112309 Hom.: 0 Cov.: 24 AF XY: 0.000696 AC XY: 24 AN XY: 34489

Gnomad4 AFR AF: 0.000388

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: 0.00107

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000794 Hom.: 32

Bravo AF: 0.000465

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.000445 AC: 54

EpiCase AF: 0.000763

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.79G>A (p.V27M) 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 79, causing the valine (V) at amino acid position 27 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PLXNA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 19, 2019

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	0.087
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	4.7
Dann	Benign	0.91
FATHMM_MKL	Benign	0.10	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.92	T
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.53	N
REVEL	Benign	0.0090
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Vest4		0.076
MVP		0.16
ClinPred		0.0053	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.39

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: rs149048914; hg19: chrX-153688602; COSMIC: COSV63755740; COSMIC: COSV63755740;