14-104930075-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_138790.5(PLD4):c.687T>G(p.Ser229Arg) 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 pathogenic 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: 0.0710

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.925

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLD4	NM_138790.5	c.687T>G	p.Ser229Arg	missense_variant	6/11	ENST00000392593.9
PLD4	NM_001308174.2	c.708T>G	p.Ser236Arg	missense_variant	6/11
PLD4	XM_011536411.3	c.708T>G	p.Ser236Arg	missense_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLD4	ENST00000392593.9	c.687T>G	p.Ser229Arg	missense_variant	6/11	1	NM_138790.5	P2
PLD4	ENST00000540372.5	c.708T>G	p.Ser236Arg	missense_variant	6/11	2		A2
PLD4	ENST00000649344.1	c.687T>G	p.Ser229Arg	missense_variant	6/11
PLD4	ENST00000557573.1	c.681T>G	p.Ser227Arg	missense_variant	6/7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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

Sep 20, 2023

The c.687T>G (p.S229R) alteration is located in exon 6 (coding exon 5) of the PLD4 gene. This alteration results from a T to G substitution at nucleotide position 687, causing the serine (S) at amino acid position 229 to be replaced by an arginine (R). 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	0.99
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.43	N
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Uncertain	0.10	D
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.63	T
Polyphen		1.0	.;D;D;.
Vest4		0.98, 0.98
MutPred		0.83		.;Gain of catalytic residue at I232 (P = 0);.;.;
MVP		0.63
MPC		0.50
ClinPred		1.0	D
GERP RS		1.4
Varity_R		0.89
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105396412;