X-154460253-C-T

Variant names:

• chrX-154460253-C-T
• rs782215325
• NM_017514.5:c.70C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017514.5(PLXNA3):​c.70C>T​(p.Arg24Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000414 in 1,208,015 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000043 (0 hom. 13 hem.)
• Consequence: PLXNA3 NM_017514.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.63

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20540863).
• BS2: High Hemizygotes in GnomAdExome4 at 13 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA3	NM_017514.5	c.70C>T	p.Arg24Cys	missense_variant	Exon 2 of 33	ENST00000369682.4	NP_059984.3
PLXNA3	XM_047442247.1	c.70C>T	p.Arg24Cys	missense_variant	Exon 2 of 22		XP_047298203.1
PLXNA3	XR_007068193.1	n.245C>T		non_coding_transcript_exon_variant	Exon 2 of 32
PLXNA3	XR_430556.4	n.245C>T		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	c.70C>T	p.Arg24Cys	missense_variant	Exon 2 of 33	1	NM_017514.5	ENSP00000358696.3
PLXNA3	ENST00000495040.1	n.146-846C>T		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112381 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34551

Gnomad AFR AF: 0.0000323

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: 0.000161

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000665 AC: 12 AN: 180346 Hom.: 0 AF XY: 0.0000605 AC XY: 4 AN XY: 66132

Gnomad AFR exome AF: 0.0000768

Gnomad AMR exome AF: 0.0000366

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000726

Gnomad SAS exome AF: 0.000105

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000753

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.0000429 AC: 47 AN: 1095634 Hom.: 0 Cov.: 31 AF XY: 0.0000360 AC XY: 13 AN XY: 361586

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000568

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000993

Gnomad4 SAS exome AF: 0.0000924

Gnomad4 FIN exome AF: 0.0000252

Gnomad4 NFE exome AF: 0.0000404

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112381 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34551

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000161

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000742 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.70C>T (p.R24C) alteration is located in exon 2 (coding exon 1) of the PLXNA3 gene. This alteration results from a C to T substitution at nucleotide position 70, causing the arginine (R) at amino acid position 24 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PLXNA3-related disorder Uncertain:1

Feb 07, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PLXNA3 c.70C>T variant is predicted to result in the amino acid substitution p.Arg24Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of South Asian descent in gnomAD. 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	0.21
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	22
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.18
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.027	D
Vest4		0.31
MutPred		0.64		Loss of methylation at R24 (P = 0.0322);
MVP		0.30
ClinPred		0.079	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs782215325; hg19: chrX-153688593; COSMIC: COSV100859888; COSMIC: COSV100859888;