3-171603233-C-T

Position:

• chr3-171603233-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002662.5(PLD1):​c.3070G>A​(p.Val1024Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,613,990 control chromosomes in the GnomAD database, including 28 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (18 hom.)
• Consequence: PLD1 NM_002662.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.37

Genes affected

PLD1 (HGNC:9067): (phospholipase D1) This gene encodes a phosphatidylcholine-specific phospholipase which catalyzes the hydrolysis of phosphatidylcholine in order to yield phosphatidic acid and choline. The enzyme may play a role in signal transduction and subcellular trafficking. Alternative splicing results in multiple transcript variants with both catalytic and regulatory properties. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025039613).
• BP6: Variant 3-171603233-C-T is Benign according to our data. Variant chr3-171603233-C-T is described in ClinVar as [Benign]. Clinvar id is 708886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00685 (1043/152264) while in subpopulation AFR AF= 0.0198 (824/41570). AF 95% confidence interval is 0.0187. There are 10 homozygotes in gnomad4. There are 502 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD1	NM_002662.5	c.3070G>A	p.Val1024Ile	missense_variant	27/27	ENST00000351298.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD1	ENST00000351298.9	c.3070G>A	p.Val1024Ile	missense_variant	27/27	1	NM_002662.5	A1
PLD1	ENST00000356327.9	c.2956G>A	p.Val986Ile	missense_variant	26/26	1		P4

Frequencies

GnomAD3 genomes AF: 0.00681 AC: 1036 AN: 152146 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00242 AC: 607 AN: 251102 Hom.: 3 AF XY: 0.00216 AC XY: 293 AN XY: 135706

Gnomad AFR exome AF: 0.0187

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000588

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.00253 AC: 3705 AN: 1461726 Hom.: 18 Cov.: 31 AF XY: 0.00240 AC XY: 1742 AN XY: 727168

Gnomad4 AFR exome AF: 0.0219

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000649

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.00235

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152264 Hom.: 10 Cov.: 32 AF XY: 0.00674 AC XY: 502 AN XY: 74448

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00310 Hom.: 3

Bravo AF: 0.00773

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.0193 AC: 85

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00268 AC: 326

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00240

EpiControl AF: 0.00231

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

- -

PLD1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 10, 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	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.6
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.52	T;T
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.14
Sift	Benign	0.60	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	.;B
Vest4		0.053
MVP		0.20
MPC		0.083
ClinPred		0.0018	T
GERP RS		3.7
Varity_R		0.037
gMVP		0.14

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: rs9827333; hg19: chr3-171321023;