3-129585954-G-A

Position:

• chr3-129585954-G-A

Variant summary

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

The NM_015103.3(PLXND1):​c.1849C>T​(p.Pro617Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0389 in 1,613,970 control chromosomes in the GnomAD database, including 1,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.049 (263 hom., cov: 33)
  • Exomes 𝑓: 0.038 (1594 hom.)
• Consequence: PLXND1 NM_015103.3 missense, splice_region
• Scores: Splicing: ADA: 0.006426
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.09

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=0.0015977621).
• BP6: Variant 3-129585954-G-A is Benign according to our data. Variant chr3-129585954-G-A is described in ClinVar as [Benign]. Clinvar id is 3056786.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.109 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLXND1	NM_015103.3	c.1849C>T	p.Pro617Ser	missense_variant, splice_region_variant	5/36	ENST00000324093.9	NP_055918.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLXND1	ENST00000324093.9	c.1849C>T	p.Pro617Ser	missense_variant, splice_region_variant	5/36	1	NM_015103.3	ENSP00000317128	P1
PLXND1	ENST00000505237.2	c.505C>T	p.Pro169Ser	missense_variant	4/4	5		ENSP00000426241
PLXND1	ENST00000505665.5	c.328C>T	p.Pro110Ser	missense_variant, splice_region_variant, NMD_transcript_variant	3/5	5		ENSP00000423832

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7427 AN: 152202 Hom.: 264 Cov.: 33

Gnomad AFR AF: 0.0678

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.118

Gnomad SAS AF: 0.0830

Gnomad FIN AF: 0.0346

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0306

Gnomad OTH AF: 0.0549

GnomAD3 exomes AF: 0.0512 AC: 12874 AN: 251336 Hom.: 502 AF XY: 0.0525 AC XY: 7132 AN XY: 135864

Gnomad AFR exome AF: 0.0679

Gnomad AMR exome AF: 0.0272

Gnomad ASJ exome AF: 0.130

Gnomad EAS exome AF: 0.126

Gnomad SAS exome AF: 0.0793

Gnomad FIN exome AF: 0.0369

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0556

GnomAD4 exome AF: 0.0379 AC: 55342 AN: 1461650 Hom.: 1594 Cov.: 33 AF XY: 0.0395 AC XY: 28755 AN XY: 727136

Gnomad4 AFR exome AF: 0.0722

Gnomad4 AMR exome AF: 0.0281

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.0816

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0276

Gnomad4 OTH exome AF: 0.0517

GnomAD4 genome AF: 0.0488 AC: 7438 AN: 152320 Hom.: 263 Cov.: 33 AF XY: 0.0502 AC XY: 3741 AN XY: 74486

Gnomad4 AFR AF: 0.0680

Gnomad4 AMR AF: 0.0363

Gnomad4 ASJ AF: 0.132

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0831

Gnomad4 FIN AF: 0.0346

Gnomad4 NFE AF: 0.0306

Gnomad4 OTH AF: 0.0562

Alfa AF: 0.0427 Hom.: 447

Bravo AF: 0.0496

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.0654 AC: 288

ESP6500EA AF: 0.0340 AC: 292

ExAC AF: 0.0513 AC: 6225

Asia WGS AF: 0.107 AC: 371 AN: 3478

EpiCase AF: 0.0352

EpiControl AF: 0.0362

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	0.094
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	17
DANN	Benign	0.72
DEOGEN2	Benign	0.050	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.63	T;T
MetaRNN	Benign	0.0016	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.20	N;.
MutationTaster	Benign	0.36	P;P
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.020	N;N
REVEL	Benign	0.047
Sift	Benign	0.67	T;D
Sift4G	Benign	0.83	T;D
Polyphen		0.0	B;.
Vest4		0.042
MPC		0.29
ClinPred		0.0052	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.030
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0064
dbscSNV1_RF	Benign	0.25
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: rs2285372; hg19: chr3-129304797; COSMIC: COSV60709423;