Genetic Variant PLXNA3:p.Ala17GlyfsTer39 (chrX-154460224-T-TG) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_017514.5(PLXNA3):c.49dupG(p.Ala17GlyfsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,080,797 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 25)

Exomes 𝑓: 0.000062 ( 0 hom. 3 hem. )

Failed GnomAD Quality Control

Consequence

PLXNA3
NM_017514.5 frameshift

Scores

Not classified

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.0630

Publications

6 publications found

Variant links:

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]

PLXNA3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 3 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.49dupG	p.Ala17GlyfsTer39	frameshift	Exon 2 of 33	NP_059984.3	P51805

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLXNA3	ENST00000369682.4	TSL:1 MANE Select	c.49dupG	p.Ala17GlyfsTer39	frameshift	Exon 2 of 33	ENSP00000358696.3	P51805
PLXNA3	ENST00000937806.1		c.49dupG	p.Ala17GlyfsTer39	frameshift	Exon 2 of 33	ENSP00000607865.1
PLXNA3	ENST00000955276.1		c.49dupG	p.Ala17GlyfsTer39	frameshift	Exon 2 of 33	ENSP00000625335.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

111178

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000321

AC:

AN:

168147

AF XY:

0.0000338

show subpopulations

Gnomad AFR exome

AF:

0.000731

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000296

Gnomad EAS exome

AF:

0.0000759

Gnomad FIN exome

AF:

0.000214

Gnomad NFE exome

AF:

0.000514

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000620

AC:

AN:

1080797

Hom.:

Cov.:

AF XY:

0.00000849

AC XY:

AN XY:

353511

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000384

AC:

AN:

26039

American (AMR)

AF:

0.00

AC:

AN:

34977

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19167

East Asian (EAS)

AF:

0.00

AC:

AN:

30031

South Asian (SAS)

AF:

0.0000374

AC:

AN:

53453

European-Finnish (FIN)

AF:

0.000230

AC:

AN:

39157

Middle Eastern (MID)

AF:

0.000258

AC:

AN:

3873

European-Non Finnish (NFE)

AF:

0.0000640

AC:

AN:

828596

Other (OTH)

AF:

0.0000220

AC:

AN:

45504

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.270

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

111178

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33620

African (AFR)

AF:

0.00

AC:

AN:

30597

American (AMR)

AF:

0.00

AC:

AN:

10603

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2613

East Asian (EAS)

AF:

0.00

AC:

AN:

3544

South Asian (SAS)

AF:

0.00

AC:

AN:

2675

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6074

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52683

Other (OTH)

AF:

0.00

AC:

AN:

1486

Alfa

AF:

0.00254

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PLXNA3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.063

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over