chr8-51820467-G-T

Position:

• chr8-51820467-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_052937.4(PCMTD1):​c.958C>A​(p.His320Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PCMTD1 NM_052937.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.40

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05732006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCMTD1	NM_052937.4	c.958C>A	p.His320Asn	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.958C>A	p.His320Asn	missense_variant	6/6	2	NM_052937.4	ENSP00000428099.1
PCMTD1	ENST00000544451.2	c.730C>A	p.His244Asn	missense_variant	4/4	1		ENSP00000444026.1
PCMTD1	ENST00000360540.9	c.958C>A	p.His320Asn	missense_variant	7/7	5		ENSP00000353739.5
PCMTD1	ENST00000519559.1	n.884C>A		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000577 AC: 7

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 09, 2024

The c.958C>A (p.H320N) alteration is located in exon 6 (coding exon 5) of the PCMTD1 gene. This alteration results from a C to A substitution at nucleotide position 958, causing the histidine (H) at amino acid position 320 to be replaced by an asparagine (N). 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	0.057
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	2.3
DANN	Benign	0.52
DEOGEN2	Benign	0.016	T;T;T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.073	T;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.057	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	.;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.045
Sift	Benign	0.32	T;T;T
Sift4G	Benign	0.49	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.12
MutPred		0.14		.;Loss of helix (P = 0.079);Loss of helix (P = 0.079);
MVP		0.27
MPC		.;2.6715660745E-4;.
ClinPred		0.027	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.032
gMVP		0.21

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: rs769943059; hg19: chr8-52733027;