X-154460254-G-A

Variant names:

• chrX-154460254-G-A
• rs149878050
• NM_017514.5:c.71G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate 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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R24C) has been classified as Uncertain significance.

• 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, single submitter B:2
• Conservation: PhyloP100: 0.252
• Publications: 0 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: Benign. The variant received -10 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 VariationId is 720976.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 66 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.71G>A	p.Arg24His	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.71G>A	p.Arg24His	missense	Exon 2 of 33	ENSP00000358696.3	P51805
	PLXNA3	ENST00000937806.1		c.71G>A	p.Arg24His	missense	Exon 2 of 33	ENSP00000607865.1
	PLXNA3	ENST00000955276.1		c.71G>A	p.Arg24His	missense	Exon 2 of 33	ENSP00000625335.1

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 258 AN: 112243 Hom.: 1 Cov.: 25

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

GnomAD2 exomes AF: 0.000754 AC: 136 AN: 180395 AF XY: 0.000484

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 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

African (AFR) AF: 0.00740 AC: 195 AN: 26366

American (AMR) AF: 0.000881 AC: 31 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19357

East Asian (EAS) AF: 0.00 AC: 0 AN: 30197

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54095

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39737

Middle Eastern (MID) AF: 0.000993 AC: 4 AN: 4029

European-Non Finnish (NFE) AF: 0.0000202 AC: 17 AN: 840874

Other (OTH) AF: 0.000804 AC: 37 AN: 46012

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

African (AFR) AF: 0.00724 AC: 224 AN: 30939

American (AMR) AF: 0.00288 AC: 31 AN: 10751

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2711

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6175

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53110

Other (OTH) AF: 0.00198 AC: 3 AN: 1518

Alfa AF: 0.000775 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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		0.25
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
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs149878050; hg19: chrX-153688594;