Genetic Variant PLD4:p.Arg56Cys (chr14-104927748-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_138790.5(PLD4):c.166C>T(p.Arg56Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,598,444 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R56G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

PLD4
NM_138790.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.415

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07211247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138790.5. 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
	PLD4	NM_138790.5	MANE Select	c.166C>T	p.Arg56Cys	missense	Exon 3 of 11	NP_620145.2	Q96BZ4
	PLD4	NM_001308174.2		c.187C>T	p.Arg63Cys	missense	Exon 3 of 11	NP_001295103.1	F5H2B5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PLD4	ENST00000392593.9	TSL:1 MANE Select	c.166C>T	p.Arg56Cys	missense	Exon 3 of 11	ENSP00000376372.5	Q96BZ4
PLD4	ENST00000540372.5	TSL:2	c.187C>T	p.Arg63Cys	missense	Exon 3 of 11	ENSP00000438677.1	F5H2B5
PLD4	ENST00000862746.1		c.166C>T	p.Arg56Cys	missense	Exon 3 of 11	ENSP00000532805.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000478

GnomAD2 exomes

AF:

0.0000178

AC:

AN:

224668

AF XY:

0.0000163

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000590

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000124

AC:

AN:

1446246

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

718850

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

43470

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25904

East Asian (EAS)

AF:

0.0000508

AC:

AN:

39336

South Asian (SAS)

AF:

0.00

AC:

AN:

84372

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000144

AC:

AN:

1108302

Other (OTH)

AF:

0.00

AC:

AN:

59966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.000131

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68026

Other (OTH)

AF:

0.000478

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000284

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000249

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.59

DEOGEN2

Benign

0.015

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.31

M_CAP

Benign

0.0052

MetaRNN

Benign

0.072

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.41

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.79

REVEL

Benign

0.0080

Sift

Benign

0.21

Sift4G

Benign

0.19

Polyphen

0.0

Vest4

0.088

MutPred

0.43

Gain of catalytic residue at P62 (P = 0)

MVP

0.20

MPC

0.12

ClinPred

0.022

GERP RS

-1.4

Varity_R

0.047

gMVP

0.23

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.18

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over