20-5558005-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019593.5(GPCPD1):c.1769A>G(p.Asn590Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,188 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: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GPCPD1 NM_019593.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.24

Genes affected

GPCPD1 (HGNC:26957): (glycerophosphocholine phosphodiesterase 1) Predicted to enable glycerophosphocholine phosphodiesterase activity. Predicted to be involved in glycerophospholipid catabolic process. Predicted to act upstream of or within skeletal muscle tissue development. Predicted to be located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GPCPD1	NM_019593.5	c.1769A>G	p.Asn590Ser	missense_variant	19/20	ENST00000379019.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GPCPD1	ENST00000379019.7	c.1769A>G	p.Asn590Ser	missense_variant	19/20	1	NM_019593.5	P1
GPCPD1	ENST00000418646.5	c.545A>G	p.Asn182Ser	missense_variant	6/7	5
GPCPD1	ENST00000481038.5	n.3177A>G		non_coding_transcript_exon_variant	14/15	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450188 Hom.: 0 Cov.: 26 AF XY: 0.00000277 AC XY: 2 AN XY: 722322

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: 0.00000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Nov 07, 2023

The c.1769A>G (p.N590S) alteration is located in exon 19 (coding exon 18) of the GPCPD1 gene. This alteration results from a A to G substitution at nucleotide position 1769, causing the asparagine (N) at amino acid position 590 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	0.12
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
Cadd	Uncertain	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.43		Gain of phosphorylation at N590 (P = 0.0744);
MVP		0.42
MPC		1.2
ClinPred		0.99	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.84

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

LitVar

Other links and lift over

dbSNP: rs1985874042; hg19: chr20-5538651;