Genetic Variant PLXND1:p.His1694Leu (chr3-129560382-T-A) – 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_015103.3(PLXND1):c.5081A>T(p.His1694Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H1694R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PLXND1
NM_015103.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.99

Publications

1 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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.5081A>T	p.His1694Leu	missense	Exon 31 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.5081A>T	p.His1694Leu	missense	Exon 31 of 36	ENSP00000317128.4	Q9Y4D7-1
PLXND1	ENST00000512744.5	TSL:1	n.863A>T		non_coding_transcript_exon	Exon 8 of 13	ENSP00000426540.1	H0YAB2
PLXND1	ENST00000891948.1		c.4841A>T	p.His1614Leu	missense	Exon 29 of 34	ENSP00000562007.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.27

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.61

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

PhyloP100

5.0

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.0

REVEL

Benign

0.23

Sift

Benign

0.037

Sift4G

Uncertain

0.024

Polyphen

0.99

Vest4

0.60

MutPred

0.47

Gain of glycosylation at S1693 (P = 0.0025)

MVP

0.39

MPC

1.8

ClinPred

0.98

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.49

Mutation Taster

=44/56

disease causing

(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