rs12317552

Variant names:

• chr12-62646830-C-T
• rs12317552
• NM_020700.2:c.*1659G>A

Variant summary

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

The NM_020700.2(PPM1H):​c.*1659G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,184 control chromosomes in the GnomAD database, including 1,699 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.11 (1699 hom., cov: 32)
  • Exomes 𝑓: 0.056 (0 hom.)
• Consequence: PPM1H NM_020700.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.489
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1H	NM_020700.2	c.*1659G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000228705.7	NP_065751.1
PPM1H	XM_011538578.3	c.*1659G>A		3_prime_UTR_variant	Exon 10 of 10		XP_011536880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1H	ENST00000228705.7	c.*1659G>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_020700.2	ENSP00000228705.5

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16934 AN: 152030 Hom.: 1693 Cov.: 32

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0546

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.0201

Gnomad SAS AF: 0.0395

Gnomad FIN AF: 0.0561

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0524

Gnomad OTH AF: 0.0880

GnomAD4 exome AF: 0.0556 AC: 2 AN: 36 Hom.: 0 Cov.: 0 AF XY: 0.0357 AC XY: 1 AN XY: 28

⚠️ 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: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.500 AC: 1 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 24

Other (OTH) AF: 0.167 AC: 1 AN: 6

⚠️ 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: 0.111 AC: 16950 AN: 152148 Hom.: 1699 Cov.: 32 AF XY: 0.107 AC XY: 7997 AN XY: 74392

African (AFR) AF: 0.267 AC: 11081 AN: 41472

American (AMR) AF: 0.0545 AC: 833 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 348 AN: 3466

East Asian (EAS) AF: 0.0199 AC: 103 AN: 5172

South Asian (SAS) AF: 0.0391 AC: 189 AN: 4834

European-Finnish (FIN) AF: 0.0561 AC: 594 AN: 10594

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.0524 AC: 3562 AN: 68000

Other (OTH) AF: 0.0866 AC: 183 AN: 2114

Alfa AF: 0.0711 Hom.: 788

Bravo AF: 0.120

Asia WGS AF: 0.0460 AC: 159 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.7
DANN	Benign	0.49
PhyloP100		0.49
Mutation Taster		=100/0	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: rs12317552; hg19: chr12-63040610;