X-154460253-C-T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24H) has been classified as Benign.

• 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
• Publications: 1 publications found

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

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017514.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNA3	NM_017514.5	MANE Select	c.70C>T	p.Arg24Cys	missense	Exon 2 of 33	NP_059984.3	P51805

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXNA3	ENST00000369682.4	TSL:1 MANE Select	c.70C>T	p.Arg24Cys	missense	Exon 2 of 33	ENSP00000358696.3	P51805
	PLXNA3	ENST00000937806.1		c.70C>T	p.Arg24Cys	missense	Exon 2 of 33	ENSP00000607865.1
	PLXNA3	ENST00000955276.1		c.70C>T	p.Arg24Cys	missense	Exon 2 of 33	ENSP00000625335.1

Frequencies

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

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

GnomAD2 exomes AF: 0.0000665 AC: 12 AN: 180346 AF XY: 0.0000605

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26357

American (AMR) AF: 0.0000568 AC: 2 AN: 35188

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19354

East Asian (EAS) AF: 0.0000993 AC: 3 AN: 30201

South Asian (SAS) AF: 0.0000924 AC: 5 AN: 54092

European-Finnish (FIN) AF: 0.0000252 AC: 1 AN: 39727

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4031

European-Non Finnish (NFE) AF: 0.0000404 AC: 34 AN: 840678

Other (OTH) AF: 0.0000435 AC: 2 AN: 46006

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

African (AFR) AF: 0.0000323 AC: 1 AN: 30923

American (AMR) AF: 0.00 AC: 0 AN: 10743

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.00 AC: 0 AN: 2736

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53132

Other (OTH) AF: 0.00 AC: 0 AN: 1500

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000742 AC: 9

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)
-	1	-	PLXNA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.6
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
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs782215325; hg19: chrX-153688593; COSMIC: COSV100859888; COSMIC: COSV100859888;