rs35880504

Variant names:

• chrX-154460195-C-G
• rs35880504
• NM_017514.5:c.12C>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_017514.5(PLXNA3):​c.12C>G​(p.Val4Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,201,876 control chromosomes in the GnomAD database, including 20 homozygotes. There are 564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0089 (8 hom., 271 hem., cov: 24)
  • Exomes 𝑓: 0.00096 (12 hom. 293 hem.)
• Consequence: PLXNA3 NM_017514.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.406

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-154460195-C-G is Benign according to our data. Variant chrX-154460195-C-G is described in ClinVar as [Benign]. Clinvar id is 777847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.406 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00892 (1005/112691) while in subpopulation AFR AF= 0.0302 (938/31086). AF 95% confidence interval is 0.0286. There are 8 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXNA3	NM_017514.5	c.12C>G	p.Val4Val	synonymous_variant	Exon 2 of 33	ENST00000369682.4	NP_059984.3
PLXNA3	XM_047442247.1	c.12C>G	p.Val4Val	synonymous_variant	Exon 2 of 22		XP_047298203.1
PLXNA3	XR_007068193.1	n.187C>G		non_coding_transcript_exon_variant	Exon 2 of 32
PLXNA3	XR_430556.4	n.187C>G		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.12C>G	p.Val4Val	synonymous_variant	Exon 2 of 33	1	NM_017514.5	ENSP00000358696.3
PLXNA3	ENST00000495040.1	n.146-904C>G		intron_variant	Intron 1 of 1	5

Frequencies

GnomAD3 genomes AF: 0.00890 AC: 1002 AN: 112643 Hom.: 8 Cov.: 24 AF XY: 0.00773 AC XY: 269 AN XY: 34801

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00437

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: 0.0000564

Gnomad OTH AF: 0.0113

GnomAD3 exomes AF: 0.00246 AC: 431 AN: 175330 Hom.: 4 AF XY: 0.00171 AC XY: 108 AN XY: 63240

Gnomad AFR exome AF: 0.0303

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000137

Gnomad NFE exome AF: 0.0000907

Gnomad OTH exome AF: 0.000690

GnomAD4 exome AF: 0.000961 AC: 1047 AN: 1089185 Hom.: 12 Cov.: 30 AF XY: 0.000823 AC XY: 293 AN XY: 356133

Gnomad4 AFR exome AF: 0.0309

Gnomad4 AMR exome AF: 0.00182

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.000103

Gnomad4 NFE exome AF: 0.0000694

Gnomad4 OTH exome AF: 0.00216

GnomAD4 genome AF: 0.00892 AC: 1005 AN: 112691 Hom.: 8 Cov.: 24 AF XY: 0.00777 AC XY: 271 AN XY: 34861

Gnomad4 AFR AF: 0.0302

Gnomad4 AMR AF: 0.00436

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.0111

Alfa AF: 0.00460 Hom.: 22

Bravo AF: 0.00966

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Dec 03, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

PLXNA3-related disorder Benign:1

Sep 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35880504; hg19: chrX-153688535;