chr3-129586617-C-T

Variant names:

• chr3-129586617-C-T
• rs2301572
• NM_015103.3:c.1591G>A

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 11 publications found

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]

PLXND1 Gene-Disease associations (from GenCC):

• congenital heart defects, multiple types, 9

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Mobius syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet
• persistent truncus arteriosus

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015103.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXND1	NM_015103.3	MANE Select	c.1591G>A	p.Gly531Ser	missense	Exon 3 of 36	NP_055918.3	Q9Y4D7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLXND1	ENST00000324093.9	TSL:1 MANE Select	c.1591G>A	p.Gly531Ser	missense	Exon 3 of 36	ENSP00000317128.4	Q9Y4D7-1
	PLXND1	ENST00000891948.1		c.1591G>A	p.Gly531Ser	missense	Exon 3 of 34	ENSP00000562007.1
	PLXND1	ENST00000505237.2	TSL:5	c.280G>A	p.Gly94Ser	missense	Exon 2 of 4	ENSP00000426241.2	H0YA64

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

GnomAD2 exomes AF: 0.0557 AC: 10429 AN: 187268 AF XY: 0.0564

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 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

African (AFR) AF: 0.121 AC: 3999 AN: 33012

American (AMR) AF: 0.0324 AC: 1220 AN: 37702

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 3395 AN: 25292

East Asian (EAS) AF: 0.121 AC: 4631 AN: 38224

South Asian (SAS) AF: 0.0816 AC: 6595 AN: 80818

European-Finnish (FIN) AF: 0.0368 AC: 1866 AN: 50646

Middle Eastern (MID) AF: 0.0904 AC: 517 AN: 5716

European-Non Finnish (NFE) AF: 0.0278 AC: 30348 AN: 1091090

Other (OTH) AF: 0.0562 AC: 3319 AN: 59026

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

African (AFR) AF: 0.113 AC: 4691 AN: 41512

American (AMR) AF: 0.0428 AC: 655 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 459 AN: 3472

East Asian (EAS) AF: 0.118 AC: 609 AN: 5180

South Asian (SAS) AF: 0.0836 AC: 402 AN: 4808

European-Finnish (FIN) AF: 0.0345 AC: 366 AN: 10614

Middle Eastern (MID) AF: 0.0788 AC: 23 AN: 292

European-Non Finnish (NFE) AF: 0.0309 AC: 2098 AN: 67978

Other (OTH) AF: 0.0669 AC: 141 AN: 2108

Alfa AF: 0.0454 Hom.: 1085

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

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PLXND1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.99
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.14	N
LIST_S2	Uncertain	0.86	D
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.85	N
PhyloP100		2.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.052
Sift	Benign	0.67	T
Sift4G	Benign	0.81	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
Mutation Taster		=87/13	polymorphism (auto)

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

Other links and lift over

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