10-20046870-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032812.9(PLXDC2):c.326A>T(p.Glu109Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,451,176 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: PLXDC2 NM_032812.9 missense, splice_region
• Scores: Splicing: ADA: 0.6537
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.94

Genes affected

PLXDC2 (HGNC:21013): (plexin domain containing 2) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXDC2	NM_032812.9	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	3/14	ENST00000377252.5
PLXDC2	XM_011519750.3	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	3/14
PLXDC2	NM_001282736.2	c.325-21300A>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXDC2	ENST00000377252.5	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	3/14	1	NM_032812.9	P1
PLXDC2	ENST00000377242.7	c.325-21300A>T		intron_variant		1
PLXDC2	ENST00000377238.2	n.101A>T		splice_region_variant, non_coding_transcript_exon_variant	2/13	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451176 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 721852

Gnomad4 AFR exome AF: 0.0000304

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2022

The c.326A>T (p.E109V) alteration is located in exon 3 (coding exon 3) of the PLXDC2 gene. This alteration results from a A to T substitution at nucleotide position 326, causing the glutamic acid (E) at amino acid position 109 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.26
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.013	D
Polyphen		0.24	B
Vest4		0.84
MutPred		0.36		Loss of disorder (P = 0.023);
MVP		0.22
MPC		0.20
ClinPred		0.97	D
GERP RS		5.3
Varity_R		0.35
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.65
dbscSNV1_RF	Pathogenic	0.78
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: rs1835806907; hg19: chr10-20335799;