8-51820543-C-G

Position:

• chr8-51820543-C-G

Variant summary

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

The NM_052937.4(PCMTD1):​c.882G>C​(p.Gln294His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,042 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PCMTD1 NM_052937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

Genes affected

PCMTD1 (HGNC:30483): (protein-L-isoaspartate (D-aspartate) O-methyltransferase domain containing 1) Predicted to enable protein-L-isoaspartate (D-aspartate) O-methyltransferase activity. Predicted to be involved in protein methylation. Predicted to be located in membrane. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

PCMTD1 (HGNC:):

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/exons	MANE	Protein	UniProt
PCMTD1	NM_052937.4	c.882G>C	p.Gln294His	missense_variant	6/6	ENST00000522514.6	NP_443169.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCMTD1	ENST00000522514.6	c.882G>C	p.Gln294His	missense_variant	6/6	2	NM_052937.4	ENSP00000428099.1
PCMTD1	ENST00000544451.2	c.654G>C	p.Gln218His	missense_variant	4/4	1		ENSP00000444026.1
PCMTD1	ENST00000360540.9	c.882G>C	p.Gln294His	missense_variant	7/7	5		ENSP00000353739.5
PCMTD1	ENST00000519559.1	n.808G>C		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460042 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726260

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: 0.0000332

GnomAD4 genome Cov.: 33

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

May 13, 2024

The c.882G>C (p.Q294H) alteration is located in exon 6 (coding exon 5) of the PCMTD1 gene. This alteration results from a G to C substitution at nucleotide position 882, causing the glutamine (Q) at amino acid position 294 to be replaced by a histidine (H). 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	0.46
BayesDel_addAF	Uncertain	0.060	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;T
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.93	D;.;D
M_CAP	Benign	0.038	D
MetaRNN	Uncertain	0.49	T;T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	.;L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.014	D;D;D
Polyphen		1.0	D;P;P
Vest4		0.64
MutPred		0.31		.;Loss of sheet (P = 3e-04);Loss of sheet (P = 3e-04);
MVP		0.50
MPC		.;2.6715660745E-4;.
ClinPred		0.73	D
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.14
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1585776703; hg19: chr8-52733103;