chr3-129586617-C-T

Position:

• chr3-129586617-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_015103.3(PLXND1):​c.1591G>A​(p.Gly531Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0415 in 1,573,692 control chromosomes in the GnomAD database, including 2,174 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G531V) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.062 (444 hom., cov: 33)
  • Exomes 𝑓: 0.039 (1730 hom.)
• Consequence: PLXND1 NM_015103.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.17

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013563931).
• BP6: Variant 3-129586617-C-T is Benign according to our data. Variant chr3-129586617-C-T is described in ClinVar as [Benign]. Clinvar id is 3055714.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXND1	NM_015103.3	c.1591G>A	p.Gly531Ser	missense_variant	3/36	ENST00000324093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXND1	ENST00000324093.9	c.1591G>A	p.Gly531Ser	missense_variant	3/36	1	NM_015103.3	P1
PLXND1	ENST00000505237.2	c.280G>A	p.Gly94Ser	missense_variant	2/4	5
PLXND1	ENST00000505665.5	c.70G>A	p.Gly24Ser	missense_variant, NMD_transcript_variant	1/5	5

Frequencies

GnomAD3 genomes AF: 0.0620 AC: 9427 AN: 152050 Hom.: 443 Cov.: 33

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0429

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.119

Gnomad SAS AF: 0.0835

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0657

GnomAD3 exomes AF: 0.0557 AC: 10429 AN: 187268 Hom.: 439 AF XY: 0.0564 AC XY: 5600 AN XY: 99278

Gnomad AFR exome AF: 0.112

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.123

Gnomad SAS exome AF: 0.0788

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0591

GnomAD4 exome AF: 0.0393 AC: 55890 AN: 1421526 Hom.: 1730 Cov.: 32 AF XY: 0.0408 AC XY: 28643 AN XY: 702854

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.0324

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0816

Gnomad4 FIN exome AF: 0.0368

Gnomad4 NFE exome AF: 0.0278

Gnomad4 OTH exome AF: 0.0562

GnomAD4 genome AF: 0.0621 AC: 9444 AN: 152166 Hom.: 444 Cov.: 33 AF XY: 0.0632 AC XY: 4702 AN XY: 74406

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0428

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.0836

Gnomad4 FIN AF: 0.0345

Gnomad4 NFE AF: 0.0309

Gnomad4 OTH AF: 0.0669

Alfa AF: 0.0446 Hom.: 591

Bravo AF: 0.0649

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.106 AC: 465

ESP6500EA AF: 0.0326 AC: 280

ExAC AF: 0.0435 AC: 5176

Asia WGS AF: 0.113 AC: 390 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

PLXND1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 24, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.056	T;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D;D
MetaRNN	Benign	0.0014	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.85	N;.
MutationTaster	Benign	0.94	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.052
Sift	Benign	0.67	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.068	B;.
Vest4		0.028
MPC		0.29
ClinPred		0.0039	T
GERP RS		1.2
Varity_R		0.045
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs2301572; hg19: chr3-129305460; COSMIC: COSV60712643; COSMIC: COSV60712643;