3-161069012-C-T

Position:

chr3-161069012-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_139245.4(PPM1L):c.938C>T(p.Ala313Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

PPM1L
NM_139245.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.54

Variant links:

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]

PPM1L links:

PPM1L (HGNC:):

PPM1L links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPM1L	NM_139245.4 linkuse as main transcript	c.938C>T	p.Ala313Val	missense_variant	4/4	ENST00000498165.6	NP_640338.2	Q5SGD2-1
PPM1L	NM_001317911.2 linkuse as main transcript	c.557C>T	p.Ala186Val	missense_variant	4/4		NP_001304840.1	Q5SGD2-3
PPM1L	NM_001317912.2 linkuse as main transcript	c.401C>T	p.Ala134Val	missense_variant	5/5		NP_001304841.1	Q5SGD2-2
PPM1L	NR_134243.2 linkuse as main transcript	n.958C>T		non_coding_transcript_exon_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PPM1L	ENST00000498165.6 linkuse as main transcript	c.938C>T	p.Ala313Val	missense_variant	4/4	1	NM_139245.4	ENSP00000417659.1	Q5SGD2-1
PPM1L	ENST00000295839.9 linkuse as main transcript	c.557C>T	p.Ala186Val	missense_variant	4/4	1		ENSP00000295839.9	Q5SGD2-3
PPM1L	ENST00000464260.5 linkuse as main transcript	c.401C>T	p.Ala134Val	missense_variant	5/5	2		ENSP00000420746.1	Q5SGD2-2
PPM1L	ENST00000480117.1 linkuse as main transcript	n.958C>T		non_coding_transcript_exon_variant	6/6	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000889

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 29, 2024

The c.938C>T (p.A313V) alteration is located in exon 4 (coding exon 4) of the PPM1L gene. This alteration results from a C to T substitution at nucleotide position 938, causing the alanine (A) at amino acid position 313 to be replaced by a valine (V). 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

0.89

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.29

T;.;.

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

D;D;D

M_CAP

Benign

0.046

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.5

D;D;D

REVEL

Benign

0.26

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.035

D;T;D

Polyphen

1.0

D;.;D

Vest4

0.74

MutPred

0.69

Loss of ubiquitination at K318 (P = 0.1351);.;.;

MVP

0.25

MPC

1.9

ClinPred

1.0

GERP RS

5.1

Varity_R

0.77

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over