12-62788329-T-C

Variant names:

• chr12-62788329-T-C
• rs377085423
• NM_020700.2:c.766A>G

Variant summary

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

The NM_020700.2(PPM1H):​c.766A>G​(p.Ile256Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000426 in 1,408,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. I256L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: PPM1H NM_020700.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.59
• Publications: 0 publications found

Genes affected

PPM1H (HGNC:18583): (protein phosphatase, Mg2+/Mn2+ dependent 1H) Enables identical protein binding activity and phosphoprotein phosphatase activity. Predicted to be involved in protein dephosphorylation. Located in cytoplasm and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

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=0.25045365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1H	NM_020700.2	c.766A>G	p.Ile256Val	missense_variant	Exon 4 of 10	ENST00000228705.7	NP_065751.1
PPM1H	XM_011538578.3	c.652A>G	p.Ile218Val	missense_variant	Exon 4 of 10		XP_011536880.1
PPM1H	XM_017019676.3	c.766A>G	p.Ile256Val	missense_variant	Exon 4 of 9		XP_016875165.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1H	ENST00000228705.7	c.766A>G	p.Ile256Val	missense_variant	Exon 4 of 10	1	NM_020700.2	ENSP00000228705.5
PPM1H	ENST00000551519.1	n.156A>G		non_coding_transcript_exon_variant	Exon 1 of 5	4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1408406 Hom.: 0 Cov.: 27 AF XY: 0.00000717 AC XY: 5 AN XY: 697456

African (AFR) AF: 0.00 AC: 0 AN: 32318

American (AMR) AF: 0.00 AC: 0 AN: 38548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25358

East Asian (EAS) AF: 0.00 AC: 0 AN: 38014

South Asian (SAS) AF: 0.00 AC: 0 AN: 80400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50912

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5658

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1078606

Other (OTH) AF: 0.00 AC: 0 AN: 58592

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.6
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.20
Sift	Benign	0.062	T
Sift4G	Benign	0.12	T
Polyphen		0.48	P
Vest4		0.41
MutPred		0.47		Loss of helix (P = 0.0626);
MVP		0.14
MPC		0.36
ClinPred		0.86	D
GERP RS		5.3
Varity_R		0.13
gMVP		0.59
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs377085423; hg19: chr12-63182109;