Genetic Variant PLXND1:p.Gly531Cys (chr3-129586617-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015103.3(PLXND1):c.1591G>T(p.Gly531Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G531S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PLXND1
NM_015103.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.17

Publications

11 publications found

Variant links:

Genes affected

PLXND1 (HGNC:9107): (plexin D1) Enables protein domain specific binding activity. Predicted to be involved in several processes, including endothelial cell migration; nervous system development; and regulation of angiogenesis. Predicted to act upstream of or within several processes, including circulatory system development; dichotomous subdivision of terminal units involved in salivary gland branching; and positive regulation of protein binding activity. Located in lamellipodium. [provided by Alliance of Genome Resources, Apr 2022]

PLXND1 Gene-Disease associations (from GenCC):

congenital heart defects, multiple types, 9
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
Mobius syndrome
Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
persistent truncus arteriosus
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

PLXND1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22154942).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015103.3. 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
	PLXND1	NM_015103.3	MANE Select	c.1591G>T	p.Gly531Cys	missense	Exon 3 of 36	NP_055918.3	Q9Y4D7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLXND1	ENST00000324093.9	TSL:1 MANE Select	c.1591G>T	p.Gly531Cys	missense	Exon 3 of 36	ENSP00000317128.4	Q9Y4D7-1
PLXND1	ENST00000891948.1		c.1591G>T	p.Gly531Cys	missense	Exon 3 of 34	ENSP00000562007.1
PLXND1	ENST00000505237.2	TSL:5	c.280G>T	p.Gly94Cys	missense	Exon 2 of 4	ENSP00000426241.2	H0YA64

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1421584

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

702886

African (AFR)

AF:

0.00

AC:

AN:

33022

American (AMR)

AF:

0.00

AC:

AN:

37704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25294

East Asian (EAS)

AF:

0.00

AC:

AN:

38232

South Asian (SAS)

AF:

0.00

AC:

AN:

80822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50650

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091114

Other (OTH)

AF:

0.00

AC:

AN:

59030

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.028

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

PhyloP100

2.2

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.8

REVEL

Benign

0.12

Sift

Uncertain

0.027

Sift4G

Uncertain

0.055

Polyphen

1.0

Vest4

0.47

MutPred

0.51

Gain of glycosylation at Y534 (P = 0.0142)

MVP

0.31

MPC

0.71

ClinPred

0.77

GERP RS

1.2

Varity_R

0.14

gMVP

0.66

Mutation Taster

=82/18

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over