14-104928832-T-C

Variant names:

• chr14-104928832-T-C
• NM_138790.5:c.368T>C

Variant summary

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

The NM_138790.5(PLD4):​c.368T>C​(p.Leu123Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLD4 NM_138790.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0590

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 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	c.368T>C	p.Leu123Pro	missense_variant	Exon 4 of 11	ENST00000392593.9	NP_620145.2
PLD4	NM_001308174.2	c.389T>C	p.Leu130Pro	missense_variant	Exon 4 of 11		NP_001295103.1
PLD4	XM_011536411.3	c.389T>C	p.Leu130Pro	missense_variant	Exon 4 of 11		XP_011534713.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PLD4	ENST00000392593.9	c.368T>C	p.Leu123Pro	missense_variant	Exon 4 of 11	1	NM_138790.5	ENSP00000376372.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459892 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726110

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.368T>C (p.L123P) alteration is located in exon 4 (coding exon 3) of the PLD4 gene. This alteration results from a T to C substitution at nucleotide position 368, causing the leucine (L) at amino acid position 123 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	Uncertain	0.55
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	.;T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.0090
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.75	T;T;T;T
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	.;.;M;.
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.7	.;D;D;D
REVEL	Benign	0.25
Sift	Benign	0.052	.;T;D;T
Sift4G	Benign	0.18	.;T;T;T
Polyphen		0.96, 0.93	.;D;P;.
Vest4		0.66, 0.65
MutPred		0.73		.;Gain of catalytic residue at A128 (P = 0.0186);.;.;
MVP		0.28
MPC		0.38
ClinPred		0.87	D
GERP RS		1.8
Varity_R		0.58
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-105395169;