12-14507038-C-T

Position:

• chr12-14507038-C-T

Variant summary

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

The NM_024829.6(PLBD1):​c.1267G>A​(p.Gly423Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000753 in 1,461,714 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000075 (0 hom.)
• Consequence: PLBD1 NM_024829.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.38

Genes affected

PLBD1 (HGNC:26215): (phospholipase B domain containing 1) Predicted to enable phospholipase activity. Predicted to be involved in phospholipid catabolic process. Located in extracellular space. [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, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PLBD1	NM_024829.6	c.1267G>A	p.Gly423Ser	missense_variant	9/11	ENST00000240617.10	NP_079105.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PLBD1	ENST00000240617.10	c.1267G>A	p.Gly423Ser	missense_variant	9/11	1	NM_024829.6	ENSP00000240617	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000753 AC: 11 AN: 1461714 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727168

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: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000301 Hom.: 0

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.1267G>A (p.G423S) alteration is located in exon 9 (coding exon 9) of the PLBD1 gene. This alteration results from a G to A substitution at nucleotide position 1267, causing the glycine (G) at amino acid position 423 to be replaced by a serine (S). 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	0.17
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.041	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-4.3	D
REVEL	Uncertain	0.49
Sift	Benign	0.046	D
Sift4G	Benign	0.085	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.74		Gain of catalytic residue at Q420 (P = 0.0059);
MVP		0.41
MPC		0.77
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.52
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: -25

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

Publications

LitVar

Other links and lift over

dbSNP: rs891870385; hg19: chr12-14659972;