NM_002662.5:c.2882+2T>C

Variant names:

• chr3-171612277-A-G
• rs1085307450
• NM_002662.5:c.2882+2T>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002662.5(PLD1):​c.2882+2T>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLD1 NM_002662.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9892
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.29
• Publications: 1 publications found

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]

PLD1 Gene-Disease associations (from GenCC):

• cardiac valvular defect, developmental

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• PLD1-related congenital heart disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-171612277-A-G is Pathogenic according to our data. Variant chr3-171612277-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 426091.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002662.5. 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
	PLD1	NM_002662.5	MANE Select	c.2882+2T>C		splice_donor intron	N/A	NP_002653.1	Q13393-1
	PLD1	NM_001130081.3		c.2768+2T>C		splice_donor intron	N/A	NP_001123553.1	Q13393-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLD1	ENST00000351298.9	TSL:1 MANE Select	c.2882+2T>C		splice_donor intron	N/A	ENSP00000342793.4	Q13393-1
	PLD1	ENST00000356327.9	TSL:1	c.2768+2T>C		splice_donor intron	N/A	ENSP00000348681.5	Q13393-2
	PLD1	ENST00000446289.1	TSL:1	c.668+2T>C		splice_donor intron	N/A	ENSP00000395556.1	H7C0L3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cardiac valvular defect, developmental (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -12
DS_DL_spliceai		0.90		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1085307450;

hg19: chr3-171330067;

COSMIC: COSV100577596;

COSMIC: COSV100577596;