6-149749761-G-T

Variant names:

• chr6-149749761-G-T
• rs758763218
• NM_001360452.2:c.-141G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001252049.1(PCMT1):​c.34G>T​(p.Asp12Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000172 in 1,394,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D12E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: PCMT1 NM_001252049.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 0 publications found

Genes affected

PCMT1 (HGNC:8728): (protein-L-isoaspartate (D-aspartate) O-methyltransferase) This gene encodes a member of the type II class of protein carboxyl methyltransferase enzymes. The encoded enzyme plays a role in protein repair by recognizing and converting D-aspartyl and L-isoaspartyl residues resulting from spontaneous deamidation back to the normal L-aspartyl form. The encoded protein may play a protective role in the pathogenesis of Alzheimer's disease, and single nucleotide polymorphisms in this gene have been associated with spina bifida and premature ovarian failure. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Oct 2011]

NUP43 (HGNC:21182): (nucleoporin 43) Bidirectional transport of macromolecules between the cytoplasm and nucleus occurs through nuclear pore complexes (NPCs) embedded in the nuclear envelope. NPCs are composed of subcomplexes, and NUP43 is part of one such subcomplex, Nup107-160 (Loiodice et al., 2004 [PubMed 15146057]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29128325).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001252049.1. 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
	PCMT1	NM_001360452.2	MANE Select	c.-141G>T		5_prime_UTR	Exon 1 of 8	NP_001347381.1	A0A384MDK7
	PCMT1	NM_001252049.1		c.34G>T	p.Asp12Tyr	missense	Exon 1 of 8	NP_001238978.1	P22061
	PCMT1	NM_001252053.1		c.34G>T	p.Asp12Tyr	missense	Exon 1 of 7	NP_001238982.1	P22061

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCMT1	ENST00000464889.7	TSL:1 MANE Select	c.-141G>T		5_prime_UTR	Exon 1 of 8	ENSP00000420813.2	P22061-1
	PCMT1	ENST00000367384.8	TSL:1	c.-141G>T		5_prime_UTR	Exon 1 of 8	ENSP00000356354.3	P22061-2
	PCMT1	ENST00000367378.6	TSL:1	c.-141G>T		5_prime_UTR	Exon 1 of 7	ENSP00000356348.2	P22061-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000172 AC: 24 AN: 1394720 Hom.: 0 Cov.: 30 AF XY: 0.0000116 AC XY: 8 AN XY: 687664

African (AFR) AF: 0.00 AC: 0 AN: 31444

American (AMR) AF: 0.00 AC: 0 AN: 35558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25112

East Asian (EAS) AF: 0.00 AC: 0 AN: 35592

South Asian (SAS) AF: 0.00 AC: 0 AN: 79104

European-Finnish (FIN) AF: 0.0000421 AC: 2 AN: 47514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5628

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1076958

Other (OTH) AF: 0.0000692 AC: 4 AN: 57810

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	18
DANN	Benign	0.97
DEOGEN2	Benign	0.011	T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.9
PrimateAI	Pathogenic	0.83	D
Sift4G	Uncertain	0.023	D
Vest4		0.44
MutPred		0.23		Gain of phosphorylation at D12 (P = 0.0388)
MVP		0.49
ClinPred		0.94	D
GERP RS		4.3
PromoterAI		-0.035	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
gMVP		0.35
Mutation Taster		=283/17	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: rs758763218; hg19: chr6-150070897;