3-160756693-G-A

Position:

• chr3-160756693-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_139245.4(PPM1L):​c.385G>A​(p.Gly129Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPM1L NM_139245.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47

Genes affected

PPM1L (HGNC:16381): (protein phosphatase, Mg2+/Mn2+ dependent 1L) The protein encoded by this gene is a magnesium or manganese-requiring phosphatase that is involved in several signaling pathways. The encoded protein downregulates apoptosis signal-regulating kinase 1, a protein that initiates a signaling cascade that leads to apoptosis when cells are subjected to cytotoxic stresses. This protein also is an endoplasmic reticulum transmembrane protein that helps regulate ceramide transport from the endoplasmic reticulum to the Golgi apparatus. Finally, this gene may be involved in adiposity since it is upregulated in adipose tissues. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity PPM1L_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1L	NM_139245.4	c.385G>A	p.Gly129Arg	missense_variant	1/4	ENST00000498165.6	NP_640338.2
PPM1L	XM_011512440.4	c.385G>A	p.Gly129Arg	missense_variant	1/3		XP_011510742.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPM1L	ENST00000498165.6	c.385G>A	p.Gly129Arg	missense_variant	1/4	1	NM_139245.4	ENSP00000417659.1
PPM1L	ENST00000497343.5	c.385G>A	p.Gly129Arg	missense_variant	1/3	2		ENSP00000420354.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 09, 2024

The c.385G>A (p.G129R) alteration is located in exon 1 (coding exon 1) of the PPM1L gene. This alteration results from a G to A substitution at nucleotide position 385, causing the glycine (G) at amino acid position 129 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	.;D
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Pathogenic	4.5	H;H
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-6.9	D;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.72		Gain of phosphorylation at T134 (P = 0.2079);Gain of phosphorylation at T134 (P = 0.2079);
MVP		0.77
MPC		2.1
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.86
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-160474481;