X-154460254-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_017514.5(PLXNA3):c.71G>A(p.Arg24His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,208,144 control chromosomes in the GnomAD database, including 2 homozygotes. There are 143 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., 66 hem., cov: 25)
  • Exomes 𝑓: 0.00026 (1 hom. 77 hem.)
• Consequence: PLXNA3 NM_017514.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.252

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004250586).
• BP6: Variant X-154460254-G-A is Benign according to our data. Variant chrX-154460254-G-A is described in ClinVar as [Benign]. Clinvar id is 720976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 65 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXNA3	NM_017514.5	c.71G>A	p.Arg24His	missense_variant	2/33	ENST00000369682.4
PLXNA3	XM_047442247.1	c.71G>A	p.Arg24His	missense_variant	2/22
PLXNA3	XR_007068193.1	n.246G>A		non_coding_transcript_exon_variant	2/32
PLXNA3	XR_430556.4	n.246G>A		non_coding_transcript_exon_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXNA3	ENST00000369682.4	c.71G>A	p.Arg24His	missense_variant	2/33	1	NM_017514.5	P1
PLXNA3	ENST00000495040.1	n.146-845G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 258 AN: 112243 Hom.: 1 Cov.: 25 AF XY: 0.00189 AC XY: 65 AN XY: 34439

Gnomad AFR AF: 0.00726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00289

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: 0.00

Gnomad OTH AF: 0.00200

GnomAD3 exomes AF: 0.000754 AC: 136 AN: 180395 Hom.: 1 AF XY: 0.000484 AC XY: 32 AN XY: 66151

Gnomad AFR exome AF: 0.00845

Gnomad AMR exome AF: 0.000695

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: 0.0000502

Gnomad OTH exome AF: 0.000674

GnomAD4 exome AF: 0.000260 AC: 285 AN: 1095849 Hom.: 1 Cov.: 31 AF XY: 0.000213 AC XY: 77 AN XY: 361787

Gnomad4 AFR exome AF: 0.00740

Gnomad4 AMR exome AF: 0.000881

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000202

Gnomad4 OTH exome AF: 0.000804

GnomAD4 genome AF: 0.00230 AC: 258 AN: 112295 Hom.: 1 Cov.: 25 AF XY: 0.00191 AC XY: 66 AN XY: 34501

Gnomad4 AFR AF: 0.00724

Gnomad4 AMR AF: 0.00288

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.000535 Hom.: 10

Bravo AF: 0.00370

ESP6500AA AF: 0.00756 AC: 29

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000783 AC: 95

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

PLXNA3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.91
Cadd	Benign	19
Dann	Uncertain	0.99
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	0.95	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.032
Sift	Benign	0.082	T
Sift4G	Benign	0.15	T
Vest4		0.11
MVP		0.21
ClinPred		0.0065	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.38

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

Other links and lift over

dbSNP: rs149878050; hg19: chrX-153688594;