chr11-74239225-T-C

Variant names:

• chr11-74239225-T-C
• rs199836683
• NM_016147.3:c.803T>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_016147.3(PPME1):​c.803T>C​(p.Ile268Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000948 in 1,613,274 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000096 (0 hom.)
• Consequence: PPME1 NM_016147.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.67

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013070762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 14		NP_001258522.1
PPME1	XM_047427116.1	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 12		XP_047283072.1
PPME1	XM_017017913.3	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.803T>C	p.Ile268Thr	missense_variant	Exon 9 of 14	1		ENSP00000381461.4

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152136 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000157 AC: 39 AN: 248374 Hom.: 0 AF XY: 0.000141 AC XY: 19 AN XY: 134742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000262

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000107

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000958 AC: 140 AN: 1461138 Hom.: 0 Cov.: 31 AF XY: 0.000100 AC XY: 73 AN XY: 726846

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000336

Gnomad4 ASJ exome AF: 0.00157

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000594

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152136 Hom.: 0 Cov.: 31 AF XY: 0.0000942 AC XY: 7 AN XY: 74318

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000244 AC: 2

ExAC AF: 0.000116 AC: 14

EpiCase AF: 0.0000545

EpiControl AF: 0.000297

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.803T>C (p.I268T) alteration is located in exon 9 (coding exon 9) of the PPME1 gene. This alteration results from a T to C substitution at nucleotide position 803, causing the isoleucine (I) at amino acid position 268 to be replaced by a threonine (T). 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	Benign	0.092
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.87
DEOGEN2	Benign	0.056	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.11
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.49	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.84	N;N
REVEL	Benign	0.070
Sift	Benign	0.72	T;T
Sift4G	Benign	0.64	T;T
Polyphen		0.0	B;.
Vest4		0.21
MVP		0.15
MPC		0.55
ClinPred		0.055	T
GERP RS		5.6
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.073
gMVP		0.18

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: rs199836683; hg19: chr11-73950270;