rs906256217

Variant names:

• chr6-149793613-A-G
• rs906256217
• NM_001360452.2:c.362A>G

Variant summary

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

The NM_001360452.2(PCMT1):​c.362A>G​(p.Asn121Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000637 in 1,571,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: PCMT1 NM_001360452.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.40
• 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]

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=0.27877152).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001360452.2. 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.362A>G	p.Asn121Ser	missense	Exon 5 of 8	NP_001347381.1	A0A384MDK7
	PCMT1	NM_001252049.1		c.536A>G	p.Asn179Ser	missense	Exon 5 of 8	NP_001238978.1	P22061
	PCMT1	NM_001252053.1		c.536A>G	p.Asn179Ser	missense	Exon 5 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.362A>G	p.Asn121Ser	missense	Exon 5 of 8	ENSP00000420813.2	P22061-1
	PCMT1	ENST00000367384.8	TSL:1	c.362A>G	p.Asn121Ser	missense	Exon 5 of 8	ENSP00000356354.3	P22061-2
	PCMT1	ENST00000367378.6	TSL:1	c.362A>G	p.Asn121Ser	missense	Exon 5 of 7	ENSP00000356348.2	P22061-1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000564 AC: 8 AN: 1418808 Hom.: 0 Cov.: 30 AF XY: 0.00000425 AC XY: 3 AN XY: 705480

African (AFR) AF: 0.000134 AC: 4 AN: 29906

American (AMR) AF: 0.00 AC: 0 AN: 34228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25234

East Asian (EAS) AF: 0.00 AC: 0 AN: 35676

South Asian (SAS) AF: 0.00 AC: 0 AN: 77988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098604

Other (OTH) AF: 0.0000681 AC: 4 AN: 58730

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152234 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

African (AFR) AF: 0.0000241 AC: 1 AN: 41462

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000189

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	0.063
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	18
DANN	Benign	0.89
DEOGEN2	Benign	0.062	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.88	L
PhyloP100		3.4
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.047
Sift	Benign	0.47	T
Sift4G	Benign	0.50	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.16
MPC		0.64
ClinPred		0.29	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.072
gMVP		0.49
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs906256217; hg19: chr6-150114749; COSMIC: COSV66302929; COSMIC: COSV66302929;