3-171692345-T-G

Variant names:

• chr3-171692345-T-G
• rs769669104
• NM_002662.5:c.1325A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_002662.5(PLD1):​c.1325A>C​(p.His442Pro) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PLD1 NM_002662.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.853
• PP5: Variant 3-171692345-T-G is Pathogenic according to our data. Variant chr3-171692345-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 426089.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLD1	NM_002662.5	c.1325A>C	p.His442Pro	missense_variant	Exon 13 of 27	ENST00000351298.9	NP_002653.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLD1	ENST00000351298.9	c.1325A>C	p.His442Pro	missense_variant	Exon 13 of 27	1	NM_002662.5	ENSP00000342793.4
PLD1	ENST00000356327.9	c.1325A>C	p.His442Pro	missense_variant	Exon 13 of 26	1		ENSP00000348681.5
PLD1	ENST00000481505.1	n.296A>C		non_coding_transcript_exon_variant	Exon 3 of 4	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cardiac valvular defect, developmental Pathogenic:1

Sep 30, 2022

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	26
DANN	Benign	0.97
DEOGEN2	Uncertain	0.47	.;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.066	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.1	M;M
PhyloP100		8.0
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.1	D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.59		Gain of catalytic residue at H442 (P = 0.0046);Gain of catalytic residue at H442 (P = 0.0046);
MVP		0.72
MPC		0.63
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.92
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs769669104; hg19: chr3-171410135;