NM_139245.4:c.575-6227C>T

Variant names:

• chr3-161059176-C-T
• rs9290065
• NM_139245.4:c.575-6227C>T

Variant summary

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

The NM_139245.4(PPM1L):​c.575-6227C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.643 in 152,058 control chromosomes in the GnomAD database, including 34,198 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 0.64 (34198 hom., cov: 32)
• Consequence: PPM1L NM_139245.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.442
• Publications: 14 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_139245.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1L	NM_139245.4	MANE Select	c.575-6227C>T		intron	N/A	NP_640338.2
	PPM1L	NM_001317911.2		c.194-6227C>T		intron	N/A	NP_001304840.1
	PPM1L	NM_001317912.2		c.38-6227C>T		intron	N/A	NP_001304841.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPM1L	ENST00000498165.6	TSL:1 MANE Select	c.575-6227C>T		intron	N/A	ENSP00000417659.1
	PPM1L	ENST00000295839.9	TSL:1	c.194-6227C>T		intron	N/A	ENSP00000295839.9
	PPM1L	ENST00000464260.5	TSL:2	c.38-6227C>T		intron	N/A	ENSP00000420746.1

Frequencies

GnomAD3 genomes AF: 0.643 AC: 97680 AN: 151940 Hom.: 34131 Cov.: 32

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.590

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.566

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.750

Gnomad FIN AF: 0.475

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.602

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.643 AC: 97809 AN: 152058 Hom.: 34198 Cov.: 32 AF XY: 0.645 AC XY: 47966 AN XY: 74322

African (AFR) AF: 0.890 AC: 36947 AN: 41518

American (AMR) AF: 0.672 AC: 10266 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 1962 AN: 3466

East Asian (EAS) AF: 0.973 AC: 5029 AN: 5168

South Asian (SAS) AF: 0.749 AC: 3608 AN: 4820

European-Finnish (FIN) AF: 0.475 AC: 5019 AN: 10562

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33010 AN: 67924

Other (OTH) AF: 0.607 AC: 1279 AN: 2108

Alfa AF: 0.548 Hom.: 78162

Bravo AF: 0.668

Asia WGS AF: 0.861 AC: 2990 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.75
DANN	Benign	0.18
PhyloP100		-0.44
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9290065; hg19: chr3-160776964;