rs10898966

Positions:

• chr11-74249059-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000328257.13(PPME1):​c.1010-1895C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,214 control chromosomes in the GnomAD database, including 2,591 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 0.18 (2591 hom., cov: 32)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: PPME1 ENST00000328257.13 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.301

Genes affected

PPME1 (HGNC:30178): (protein phosphatase methylesterase 1) This gene encodes a protein phosphatase methylesterase localized to the nucleus. The encoded protein acts on the protein phosphatase-2A catalytic subunit and supports the ERK pathway through dephosphorylation of regulatory proteins. It plays a role in malignant glioma progression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2012]

P4HA3 (HGNC:30135): (prolyl 4-hydroxylase subunit alpha 3) This gene encodes a component of prolyl 4-hydroxylase, a key enzyme in collagen synthesis composed of two identical alpha subunits and two beta subunits. The encoded protein is one of several different types of alpha subunits and provides the major part of the catalytic site of the active enzyme. In collagen and related proteins, prolyl 4-hydroxylase catalyzes the formation of 4-hydroxyproline that is essential to the proper three-dimensional folding of newly synthesized procollagen chains. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPME1	NM_016147.3	c.1010-1895C>T		intron_variant		ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.1052-1895C>T		intron_variant			NP_001258522.1
PPME1	XM_047427116.1	c.1010-1895C>T		intron_variant			XP_047283072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.1010-1895C>T		intron_variant		1	NM_016147.3	ENSP00000329867	P1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26926 AN: 152092 Hom.: 2592 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.164

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.250 AC: 1 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 1 AN XY: 4

Gnomad4 NFE exome AF: 0.250

GnomAD4 genome AF: 0.177 AC: 26935 AN: 152210 Hom.: 2591 Cov.: 32 AF XY: 0.184 AC XY: 13682 AN XY: 74414

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.109

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.298

Gnomad4 SAS AF: 0.222

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.164

Gnomad4 OTH AF: 0.141

Alfa AF: 0.166 Hom.: 535

Bravo AF: 0.157

Asia WGS AF: 0.245 AC: 848 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs10898966; hg19: chr11-73960104;