X-154460355-C-T

Position:

• chrX-154460355-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_017514.5(PLXNA3):​c.172C>T​(p.Pro58Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,209,562 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 409 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00096 (0 hom., 27 hem., cov: 25)
  • Exomes 𝑓: 0.0011 (0 hom. 382 hem.)
• Consequence: PLXNA3 NM_017514.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.255

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068145096).
• BP6: Variant X-154460355-C-T is Benign according to our data. Variant chrX-154460355-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 773622.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chrX-154460355-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 27 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXNA3	NM_017514.5	c.172C>T	p.Pro58Ser	missense_variant	2/33	ENST00000369682.4
PLXNA3	XM_047442247.1	c.172C>T	p.Pro58Ser	missense_variant	2/22
PLXNA3	XR_007068193.1	n.347C>T		non_coding_transcript_exon_variant	2/32
PLXNA3	XR_430556.4	n.347C>T		non_coding_transcript_exon_variant	2/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXNA3	ENST00000369682.4	c.172C>T	p.Pro58Ser	missense_variant	2/33	1	NM_017514.5	P1
PLXNA3	ENST00000495040.1	n.146-744C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.000959 AC: 108 AN: 112571 Hom.: 0 Cov.: 25 AF XY: 0.000778 AC XY: 27 AN XY: 34715

Gnomad AFR AF: 0.000161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000186

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00272

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.000663

GnomAD3 exomes AF: 0.000798 AC: 143 AN: 179184 Hom.: 0 AF XY: 0.000613 AC XY: 40 AN XY: 65256

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00243

Gnomad NFE exome AF: 0.00127

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00112 AC: 1224 AN: 1096938 Hom.: 0 Cov.: 31 AF XY: 0.00105 AC XY: 382 AN XY: 362712

Gnomad4 AFR exome AF: 0.000190

Gnomad4 AMR exome AF: 0.0000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00245

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.000760

GnomAD4 genome AF: 0.000959 AC: 108 AN: 112624 Hom.: 0 Cov.: 25 AF XY: 0.000776 AC XY: 27 AN XY: 34778

Gnomad4 AFR AF: 0.000161

Gnomad4 AMR AF: 0.000186

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00272

Gnomad4 NFE AF: 0.00156

Gnomad4 OTH AF: 0.000655

Alfa AF: 0.00122 Hom.: 44

Bravo AF: 0.000676

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00173 AC: 5

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000725 AC: 88

EpiCase AF: 0.000927

EpiControl AF: 0.000951

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2022

The c.172C>T (p.P58S) 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 172, causing the proline (P) at amino acid position 58 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

PLXNA3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 30, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	13
DANN	Benign	0.95
FATHMM_MKL	Benign	0.44	N
M_CAP	Benign	0.0013	T
MetaRNN	Benign	0.0068	T
MetaSVM	Benign	-0.96	T
MutationTaster	Benign	0.63	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.043
Sift	Benign	1.0	T
Sift4G	Benign	0.93	T
Vest4		0.13
MVP		0.30
ClinPred		0.0055	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.43

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: rs147019078; hg19: chrX-153688695;