Genetic Variant PLXDC2:p.Glu109Val (chr10-20046870-A-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 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

Publications

0 publications found

Variant links:

Genes affected

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

PLXDC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLXDC2	NM_032812.9 link	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	Exon 3 of 14	ENST00000377252.5	NP_116201.7	Q6UX71-1
PLXDC2	XM_011519750.3 link	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	Exon 3 of 14		XP_011518052.1
PLXDC2	NM_001282736.2 link	c.325-21300A>T		intron_variant	Intron 2 of 12		NP_001269665.1	Q6UX71-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLXDC2	ENST00000377252.5 link	c.326A>T	p.Glu109Val	missense_variant, splice_region_variant	Exon 3 of 14	1	NM_032812.9	ENSP00000366460.3	Q6UX71-1
PLXDC2	ENST00000377242.7 link	c.325-21300A>T		intron_variant	Intron 2 of 12	1		ENSP00000366450.3	Q6UX71-2
PLXDC2	ENST00000377238.2 link	n.101A>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 13	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.89e-7

AC:

AN:

1451176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721852

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32948

American (AMR)

AF:

0.00

AC:

AN:

42148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25582

East Asian (EAS)

AF:

0.00

AC:

AN:

39494

South Asian (SAS)

AF:

0.00

AC:

AN:

84102

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53132

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108154

Other (OTH)

AF:

0.00

AC:

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.50

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

PhyloP100

8.9

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

REVEL

Benign

0.26

Sift

Uncertain

0.017

Sift4G

Uncertain

0.013

Polyphen

0.24

Vest4

0.84

MutPred

0.36

Loss of disorder (P = 0.023);

MVP

0.22

MPC

0.20

ClinPred

0.97

GERP RS

5.3

Varity_R

0.35

gMVP

0.67

Mutation Taster

=48/52

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over