Genetic Variant PLD4:p.Leu167Pro (chr14-104929338-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138790.5(PLD4):c.500T>C(p.Leu167Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000571 in 1,576,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000056 ( 0 hom. )

Consequence

PLD4
NM_138790.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87

Variant links:

Genes affected

PLD4 (HGNC:23792): (phospholipase D family member 4) Predicted to enable single-stranded DNA 5'-3' exodeoxyribonuclease activity. Predicted to be involved in hematopoietic progenitor cell differentiation; phagocytosis; and regulation of cytokine production involved in inflammatory response. Predicted to be located in early endosome and endoplasmic reticulum membrane. Predicted to be active in several cellular components, including endoplasmic reticulum; phagocytic vesicle; and trans-Golgi network membrane. [provided by Alliance of Genome Resources, Apr 2022]

PLD4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PLD4	NM_138790.5 link	c.500T>C	p.Leu167Pro	missense_variant	Exon 5 of 11	ENST00000392593.9	NP_620145.2	Q96BZ4B4DI07B4DJQ6
PLD4	NM_001308174.2 link	c.521T>C	p.Leu174Pro	missense_variant	Exon 5 of 11		NP_001295103.1	B4DI07B4DJQ6F5H2B5
PLD4	XM_011536411.3 link	c.521T>C	p.Leu174Pro	missense_variant	Exon 5 of 11		XP_011534713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PLD4	ENST00000392593.9 link	c.500T>C	p.Leu167Pro	missense_variant	Exon 5 of 11	1	NM_138790.5	ENSP00000376372.5	Q96BZ4
PLD4	ENST00000540372.5 link	c.521T>C	p.Leu174Pro	missense_variant	Exon 5 of 11	2		ENSP00000438677.1	F5H2B5
PLD4	ENST00000649344.1 link	c.500T>C	p.Leu167Pro	missense_variant	Exon 5 of 11			ENSP00000497627.1	A0A3B3IT68
PLD4	ENST00000557573.1 link	c.494T>C	p.Leu165Pro	missense_variant	Exon 5 of 7	3		ENSP00000451278.1	G3V3J8

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000108

AC:

AN:

185978

Hom.:

AF XY:

0.00000996

AC XY:

AN XY:

100406

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000254

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000562

AC:

AN:

1424420

Hom.:

Cov.:

AF XY:

0.00000567

AC XY:

AN XY:

705098

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000732

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152170

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.500T>C (p.L167P) alteration is located in exon 5 (coding exon 4) of the PLD4 gene. This alteration results from a T to C substitution at nucleotide position 500, causing the leucine (L) at amino acid position 167 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

.;T;T;T

Eigen

Benign

0.039

Eigen_PC

Benign

-0.094

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.67

T;T;T;T

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.51

D;D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.1

.;.;M;.

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-5.2

.;D;D;D

REVEL

Benign

0.19

Sift

Benign

0.037

.;D;D;D

Sift4G

Uncertain

0.038

.;D;D;D

Polyphen

1.0, 0.99

.;D;D;.

Vest4

0.52, 0.53

MutPred

0.71

.;Gain of disorder (P = 0.0245);.;.;

MVP

0.095

MPC

0.58

ClinPred

0.89

GERP RS

2.8

Varity_R

0.79

gMVP

0.91

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over