chr6-149793609-G-T

Variant names:

• chr6-149793609-G-T
• rs4816
• NM_001360452.2:c.358G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001360452.2(PCMT1):​c.358G>T​(p.Val120Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000128 in 1,566,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: PCMT1 NM_001360452.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.07
• Publications: 61 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1537107).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCMT1	NM_001360452.2	MANE Select	c.358G>T	p.Val120Leu	missense	Exon 5 of 8	NP_001347381.1
	PCMT1	NM_001252049.1		c.532G>T	p.Val178Leu	missense	Exon 5 of 8	NP_001238978.1
	PCMT1	NM_001252053.1		c.532G>T	p.Val178Leu	missense	Exon 5 of 7	NP_001238982.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCMT1	ENST00000464889.7	TSL:1 MANE Select	c.358G>T	p.Val120Leu	missense	Exon 5 of 8	ENSP00000420813.2
	PCMT1	ENST00000367384.8	TSL:1	c.358G>T	p.Val120Leu	missense	Exon 5 of 8	ENSP00000356354.3
	PCMT1	ENST00000367378.6	TSL:1	c.358G>T	p.Val120Leu	missense	Exon 5 of 7	ENSP00000356348.2

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 7.07e-7 AC: 1 AN: 1414854 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 703276

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 29716

American (AMR) AF: 0.0000295 AC: 1 AN: 33942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25130

East Asian (EAS) AF: 0.00 AC: 0 AN: 35444

South Asian (SAS) AF: 0.00 AC: 0 AN: 77194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5672

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096592

Other (OTH) AF: 0.00 AC: 0 AN: 58510

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151994 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74236

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10560

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 35384

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.15	N
PhyloP100		2.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.12
Sift	Benign	0.44	T
Sift4G	Benign	0.39	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.52		Loss of ubiquitination at K125 (P = 0.1166)
MVP		0.17
MPC		0.79
ClinPred		0.53	D
GERP RS		4.6
Varity_R		0.26
gMVP		0.67
Mutation Taster		=98/2	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: rs4816; hg19: chr6-150114745;