rs4816

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr6-149793609-G-A
• chr6-149793609-G-C
• chr6-149793609-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001360452.2(PCMT1):​c.358G>A​(p.Val120Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.408 in 1,563,820 control chromosomes in the GnomAD database, including 143,604 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.53 (24834 hom., cov: 33)
  • Exomes 𝑓: 0.39 (118770 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.7449474E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

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.358G>A	p.Val120Ile	missense	Exon 5 of 8	NP_001347381.1	A0A384MDK7
	PCMT1	NM_001252049.1		c.532G>A	p.Val178Ile	missense	Exon 5 of 8	NP_001238978.1	P22061
	PCMT1	NM_001252053.1		c.532G>A	p.Val178Ile	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.358G>A	p.Val120Ile	missense	Exon 5 of 8	ENSP00000420813.2	P22061-1
	PCMT1	ENST00000367384.8	TSL:1	c.358G>A	p.Val120Ile	missense	Exon 5 of 8	ENSP00000356354.3	P22061-2
	PCMT1	ENST00000367378.6	TSL:1	c.358G>A	p.Val120Ile	missense	Exon 5 of 7	ENSP00000356348.2	P22061-1

Frequencies

GnomAD3 genomes AF: 0.533 AC: 81009 AN: 151940 Hom.: 24766 Cov.: 33

Gnomad AFR AF: 0.805

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.451

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.378

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.529

GnomAD2 exomes AF: 0.464 AC: 99400 AN: 214124 AF XY: 0.451

Gnomad AFR exome AF: 0.807

Gnomad AMR exome AF: 0.666

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.812

Gnomad FIN exome AF: 0.381

Gnomad NFE exome AF: 0.353

Gnomad OTH exome AF: 0.443

GnomAD4 exome AF: 0.394 AC: 556834 AN: 1411762 Hom.: 118770 Cov.: 31 AF XY: 0.396 AC XY: 277540 AN XY: 701586

African (AFR) AF: 0.816 AC: 24180 AN: 29644

American (AMR) AF: 0.661 AC: 22216 AN: 33620

Ashkenazi Jewish (ASJ) AF: 0.447 AC: 11181 AN: 25008

East Asian (EAS) AF: 0.770 AC: 27236 AN: 35372

South Asian (SAS) AF: 0.473 AC: 36297 AN: 76662

European-Finnish (FIN) AF: 0.379 AC: 19881 AN: 52524

Middle Eastern (MID) AF: 0.433 AC: 2451 AN: 5656

European-Non Finnish (NFE) AF: 0.354 AC: 387656 AN: 1094918

Other (OTH) AF: 0.441 AC: 25736 AN: 58358

GnomAD4 genome AF: 0.534 AC: 81138 AN: 152058 Hom.: 24834 Cov.: 33 AF XY: 0.538 AC XY: 39959 AN XY: 74332

African (AFR) AF: 0.805 AC: 33423 AN: 41494

American (AMR) AF: 0.603 AC: 9220 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 1565 AN: 3468

East Asian (EAS) AF: 0.830 AC: 4298 AN: 5178

South Asian (SAS) AF: 0.501 AC: 2420 AN: 4828

European-Finnish (FIN) AF: 0.378 AC: 3992 AN: 10550

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24627 AN: 67942

Other (OTH) AF: 0.534 AC: 1126 AN: 2110

Alfa AF: 0.426 Hom.: 35384

Bravo AF: 0.568

TwinsUK AF: 0.358 AC: 1329

ALSPAC AF: 0.353 AC: 1362

ESP6500AA AF: 0.796 AC: 3507

ESP6500EA AF: 0.373 AC: 3210

ExAC AF: 0.491 AC: 59638

Asia WGS AF: 0.665 AC: 2308 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	7.8
DANN	Benign	0.86
DEOGEN2	Benign	0.061	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.67	T
MetaRNN	Benign	6.7e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.96	N
PhyloP100		2.1
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.16	N
REVEL	Benign	0.11
Sift	Benign	0.94	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.086
MPC		0.65
ClinPred		0.0074	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.42
Mutation Taster		=99/1	polymorphism (auto)

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; COSMIC: COSV66303440; COSMIC: COSV66303440;