3-129560727-T-C

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.4994-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,571,764 control chromosomes in the GnomAD database, including 19,329 homozygotes. In-silico tool predicts 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 (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3179 hom., cov: 33)
  • Exomes 𝑓: 0.14 (16150 hom.)
• Consequence: PLXND1 NM_015103.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00005448
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.03

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 (BayesDel_noAF=-0.82).
• BP6: Variant 3-129560727-T-C is Benign according to our data. Variant chr3-129560727-T-C is described in ClinVar as [Benign]. Clinvar id is 3060610.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.286 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLXND1	NM_015103.3	c.4994-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000324093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLXND1	ENST00000324093.9	c.4994-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_015103.3	P1
PLXND1	ENST00000512744.5	c.777-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1
PLXND1	ENST00000506979.1	c.24-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5
PLXND1	ENST00000508630.1	n.216A>G		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28511 AN: 151908 Hom.: 3161 Cov.: 33

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.164

Gnomad EAS AF: 0.232

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.0836

Gnomad MID AF: 0.111

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.169 AC: 42377 AN: 251108 Hom.: 4153 AF XY: 0.167 AC XY: 22735 AN XY: 135772

Gnomad AFR exome AF: 0.289

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.163

Gnomad EAS exome AF: 0.225

Gnomad SAS exome AF: 0.236

Gnomad FIN exome AF: 0.0782

Gnomad NFE exome AF: 0.126

Gnomad OTH exome AF: 0.156

GnomAD4 exome AF: 0.141 AC: 200566 AN: 1419738 Hom.: 16150 Cov.: 26 AF XY: 0.144 AC XY: 102205 AN XY: 708680

Gnomad4 AFR exome AF: 0.291

Gnomad4 AMR exome AF: 0.219

Gnomad4 ASJ exome AF: 0.161

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.0796

Gnomad4 NFE exome AF: 0.124

Gnomad4 OTH exome AF: 0.151

GnomAD4 genome AF: 0.188 AC: 28566 AN: 152026 Hom.: 3179 Cov.: 33 AF XY: 0.191 AC XY: 14175 AN XY: 74292

Gnomad4 AFR AF: 0.291

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.164

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.0836

Gnomad4 NFE AF: 0.127

Gnomad4 OTH AF: 0.177

Alfa AF: 0.144 Hom.: 1532

Bravo AF: 0.200

Asia WGS AF: 0.223 AC: 779 AN: 3478

EpiCase AF: 0.136

EpiControl AF: 0.139

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

Jun 06, 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
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.0
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2170774; hg19: chr3-129279570; COSMIC: COSV60710818; COSMIC: COSV60710818;