rs2285372

Positions:

• chr3-129585954-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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 -14 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 criteria_provided_single_submitter, 1 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	UniProt
PLXND1	NM_015103.3	c.1849C>T	p.Pro617Ser	missense_variant, splice_region_variant	5/36	ENST00000324093.9

Ensembl

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

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: criteria provided, single submitter

Submissions by phenotype

PLXND1-related disorder Benign:1

Benign, criteria provided, single submitter

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;