20-2835502-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_022760.6(PCED1A):c.1325A>G(p.Asp442Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: PCED1A NM_022760.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.20

Genes affected

PCED1A (HGNC:16212): (PC-esterase domain containing 1A) The protein encoded by this gene is a member of the GDSL/SGNH superfamily. Members of this family are hydrolytic enzymes with esterase and lipase activity and broad substrate specificity. This protein belongs to the Pmr5-Cas1p-esterase subfamily in that it contains the catalytic triad comprised of serine, aspartate and histidine and lacks two conserved regions (glycine after strand S2 and GxND motif). A pseudogene of this gene has been identified on the long arm of chromosome 2. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33426726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCED1A	NM_022760.6	c.1325A>G	p.Asp442Gly	missense_variant	8/8	ENST00000360652.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCED1A	ENST00000360652.7	c.1325A>G	p.Asp442Gly	missense_variant	8/8	1	NM_022760.6	P1
PCED1A	ENST00000356872.7	c.1172A>G	p.Asp391Gly	missense_variant	8/8	2
PCED1A	ENST00000474714.5	c.344A>G	p.Asp115Gly	missense_variant	2/2	3
PCED1A	ENST00000487501.2	n.524A>G		non_coding_transcript_exon_variant	4/4	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250618 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727080

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: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Feb 11, 2022

The c.1325A>G (p.D442G) alteration is located in exon 8 (coding exon 7) of the PCED1A gene. This alteration results from a A to G substitution at nucleotide position 1325, causing the aspartic acid (D) at amino acid position 442 to be replaced by a glycine (G). 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	0.077
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.69	N;.
MutationTaster	Benign	0.52	N;N
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.68	N;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.060	T;D
Polyphen		1.0	D;D
Vest4		0.41
MutPred		0.26		Gain of MoRF binding (P = 0.0144);.;
MVP		0.55
MPC		0.86
ClinPred		0.30	T
GERP RS		1.5
Varity_R		0.29
gMVP		0.27

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: rs775153473; hg19: chr20-2816148;