22-21925556-C-T

Variant names:

• chr22-21925556-C-T
• rs191604554
• NM_014634.4:c.985+13G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_014634.4(PPM1F):​c.985+13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,613,610 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: PPM1F NM_014634.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.572

Genes affected

PPM1F (HGNC:19388): (protein phosphatase, Mg2+/Mn2+ dependent 1F) The protein encoded by this gene is a member of the PP2C family of Ser/Thr protein phosphatases. PP2C family members are known to be negative regulators of cell stress response pathways. This phosphatase can interact with Rho guanine nucleotide exchange factors (PIX), and thus block the effects of p21-activated kinase 1 (PAK), a protein kinase mediating biological effects downstream of Rho GTPases. Calcium/calmodulin-dependent protein kinase II gamma (CAMK2G/CAMK-II) is found to be one of the substrates of this phosphatase. The overexpression of this phosphatase or CAMK2G has been shown to mediate caspase-dependent apoptosis. An alternatively spliced transcript variant has been identified, but its full-length nature has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038058162).
• BP6: Variant 22-21925556-C-T is Benign according to our data. Variant chr22-21925556-C-T is described in ClinVar as [Benign]. Clinvar id is 1988596.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPM1F	NM_014634.4	c.985+13G>A		intron_variant	Intron 7 of 7	ENST00000263212.10	NP_055449.1
PPM1F	NM_001410836.1	c.481+13G>A		intron_variant	Intron 6 of 6		NP_001397765.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPM1F	ENST00000263212.10	c.985+13G>A		intron_variant	Intron 7 of 7	1	NM_014634.4	ENSP00000263212.5

Frequencies

GnomAD3 genomes AF: 0.00108 AC: 164 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00734

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00132 AC: 330 AN: 250610 AF XY: 0.00125

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.00111

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00102 AC: 1487 AN: 1461274 Hom.: 3 Cov.: 30 AF XY: 0.000986 AC XY: 717 AN XY: 726938

Gnomad4 AFR exome AF: 0.0000598 AC: 2 AN: 33468

Gnomad4 AMR exome AF: 0.000246 AC: 11 AN: 44700

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26132

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39690

Gnomad4 SAS exome AF: 0.000441 AC: 38 AN: 86210

Gnomad4 FIN exome AF: 0.00904 AC: 482 AN: 53304

Gnomad4 NFE exome AF: 0.000802 AC: 892 AN: 1111634

Gnomad4 Remaining exome AF: 0.000994 AC: 60 AN: 60370

GnomAD4 genome AF: 0.00108 AC: 164 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00126 AC XY: 94 AN XY: 74500

Gnomad4 AFR AF: 0.000144 AC: 0.000144314 AN: 0.000144314

Gnomad4 AMR AF: 0.000327 AC: 0.000326755 AN: 0.000326755

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207125 AN: 0.000207125

Gnomad4 FIN AF: 0.00734 AC: 0.00734049 AN: 0.00734049

Gnomad4 NFE AF: 0.00109 AC: 0.00108772 AN: 0.00108772

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000853 Hom.: 0

Bravo AF: 0.000472

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000652

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.5
DANN	Benign	0.82
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.045	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	0.0038	T
MetaSVM	Benign	-0.95	T
PROVEAN	Benign	-0.060	N
REVEL	Benign	0.065
Sift	Benign	1.0	T
Sift4G	Benign	0.78	T
Polyphen		0.024	B
Vest4		0.061
MVP		0.34
ClinPred		0.0033	T
GERP RS		1.6
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs191604554; hg19: chr22-22279929;