14-104929312-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138790.5(PLD4):c.474G>C(p.Glu158Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PLD4 NM_138790.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20489526).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD4	NM_138790.5	c.474G>C	p.Glu158Asp	missense_variant	5/11	ENST00000392593.9
PLD4	NM_001308174.2	c.495G>C	p.Glu165Asp	missense_variant	5/11
PLD4	XM_011536411.3	c.495G>C	p.Glu165Asp	missense_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD4	ENST00000392593.9	c.474G>C	p.Glu158Asp	missense_variant	5/11	1	NM_138790.5	P2
PLD4	ENST00000540372.5	c.495G>C	p.Glu165Asp	missense_variant	5/11	2		A2
PLD4	ENST00000649344.1	c.474G>C	p.Glu158Asp	missense_variant	5/11
PLD4	ENST00000557573.1	c.468G>C	p.Glu156Asp	missense_variant	5/7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000511 AC: 1 AN: 195570 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 105968

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000678

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.474G>C (p.E158D) alteration is located in exon 5 (coding exon 4) of the PLD4 gene. This alteration results from a G to C substitution at nucleotide position 474, causing the glutamic acid (E) at amino acid position 158 to be replaced by an aspartic acid (D). 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	Benign	0.29
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.52	T
Polyphen		0.36, 0.24	.;B;B;.
Vest4		0.28, 0.28
MutPred		0.32		.;Gain of catalytic residue at Q162 (P = 0.1251);.;.;
MVP		0.39
MPC		0.44
ClinPred		0.47	T
GERP RS		1.9
Varity_R		0.24
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1225570477; hg19: chr14-105395649;