11-74253493-G-T

Variant names:

• chr11-74253493-G-T
• rs200531037
• NM_016147.3:c.1144G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016147.3(PPME1):​c.1144G>T​(p.Val382Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000275 in 1,455,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V382M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: PPME1 NM_016147.3 missense, splice_region
• Scores: Splicing: ADA: 0.0003550
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.48
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13127154).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3	c.1144G>T	p.Val382Leu	missense_variant, splice_region_variant	Exon 14 of 14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.1186G>T	p.Val396Leu	missense_variant, splice_region_variant	Exon 14 of 14		NP_001258522.1
P4HA3	XR_007062475.1	n.1946-3171C>A		intron_variant	Intron 14 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.1144G>T	p.Val382Leu	missense_variant, splice_region_variant	Exon 14 of 14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.1186G>T	p.Val396Leu	missense_variant, splice_region_variant	Exon 14 of 14	1		ENSP00000381461.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455500 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724610

African (AFR) AF: 0.00 AC: 0 AN: 33332

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.00 AC: 0 AN: 86132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00000362 AC: 4 AN: 1106212

Other (OTH) AF: 0.00 AC: 0 AN: 60198

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Benign	0.10	T;.
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
PhyloP100		4.5
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.050
Sift	Benign	0.49	T;T
Sift4G	Benign	0.62	T;T
Polyphen		0.013	B;.
Vest4		0.41
MutPred		0.24		Gain of catalytic residue at V382 (P = 0.0433);.;
MVP		0.10
MPC		0.43
ClinPred		0.28	T
GERP RS		3.5
Varity_R		0.042
gMVP		0.26
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00036
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs200531037; hg19: chr11-73964538;