Genetic Variant PLXND1:p.Ile1775Phe (chr3-129558550-T-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_015103.3(PLXND1):c.5323A>T(p.Ile1775Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1775V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

PLXND1
NM_015103.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.08

Publications

0 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 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 3-129558550-T-A is Pathogenic according to our data. Variant chr3-129558550-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2445604.Status of the report is no_assertion_criteria_provided, 0 stars.

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.5323A>T	p.Ile1775Phe	missense	Exon 33 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.5323A>T	p.Ile1775Phe	missense	Exon 33 of 36	ENSP00000317128.4	Q9Y4D7-1
PLXND1	ENST00000504524.5	TSL:1	n.148A>T		non_coding_transcript_exon	Exon 1 of 4
PLXND1	ENST00000512744.5	TSL:1	n.1112A>T		non_coding_transcript_exon	Exon 10 of 13	ENSP00000426540.1	H0YAB2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital heart defects, multiple types, 9 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.29

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.10

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.7

PhyloP100

6.1

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.37

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.93

MutPred

0.67

Loss of MoRF binding (P = 0.1235)

MVP

0.61

MPC

2.1

ClinPred

0.93

GERP RS

4.7

Varity_R

0.59

gMVP

0.74

Mutation Taster

=31/69

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