12-47235794-T-A

Variant names:

• chr12-47235794-T-A
• rs759140709
• NM_138371.3:c.731T>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_138371.3(PCED1B):​c.731T>A​(p.Leu244Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L244R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: PCED1B NM_138371.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.47
• Publications: 1 publications found

Genes affected

PCED1B (HGNC:28255): (PC-esterase domain containing 1B) This gene encodes a protein that belongs to the GDSL/SGNH-like acyl-esterase family. Members of this family are hydrolases thought to function in modification of biopolymers on the cell surface. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138371.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCED1B	NM_138371.3	MANE Select	c.731T>A	p.Leu244Gln	missense	Exon 4 of 4	NP_612380.1	Q96HM7
	PCED1B	NM_001281429.2		c.731T>A	p.Leu244Gln	missense	Exon 3 of 3	NP_001268358.1	Q96HM7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCED1B	ENST00000546455.6	TSL:1 MANE Select	c.731T>A	p.Leu244Gln	missense	Exon 4 of 4	ENSP00000446688.1	Q96HM7
	PCED1B	ENST00000432328.2	TSL:3	c.731T>A	p.Leu244Gln	missense	Exon 3 of 3	ENSP00000396040.1	Q96HM7
	PCED1B	ENST00000872013.1		c.731T>A	p.Leu244Gln	missense	Exon 4 of 4	ENSP00000542072.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000512 AC: 1 AN: 195128 AF XY: 0.00000943

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432128 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 709984

African (AFR) AF: 0.00 AC: 0 AN: 32716

American (AMR) AF: 0.00 AC: 0 AN: 39606

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25592

East Asian (EAS) AF: 0.00 AC: 0 AN: 38036

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50802

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1097290

Other (OTH) AF: 0.00 AC: 0 AN: 59274

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.55		Gain of catalytic residue at L240 (P = 0.0082)
MVP		0.64
MPC		1.2
ClinPred		0.99	D
GERP RS		4.3
Varity_R		0.78
gMVP		0.84
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs759140709; hg19: chr12-47629577;