3-129558550-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM5

The NM_015103.3(PLXND1):c.5323A>G(p.Ile1775Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1775F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLXND1 NM_015103.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.08

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-129558550-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 2445604.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXND1	NM_015103.3	c.5323A>G	p.Ile1775Val	missense_variant	33/36	ENST00000324093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXND1	ENST00000324093.9	c.5323A>G	p.Ile1775Val	missense_variant	33/36	1	NM_015103.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Feb 24, 2022

The c.5323A>G (p.I1775V) alteration is located in exon 33 (coding exon 33) of the PLXND1 gene. This alteration results from a A to G substitution at nucleotide position 5323, causing the isoleucine (I) at amino acid position 1775 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	0.16
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.54	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.21
Sift	Benign	0.078	T
Sift4G	Benign	0.064	T
Polyphen		1.0	D
Vest4		0.56
MutPred		0.67		Gain of sheet (P = 0.0827);
MVP		0.38
MPC		1.5
ClinPred		0.86	D
GERP RS		4.7
Varity_R		0.15
gMVP		0.21

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-129277393;