11-74171448-C-A

Variant names:

• chr11-74171448-C-A
• NM_016147.3:c.27C>A

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.27C>A​(p.His9Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPME1 NM_016147.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0430
• 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]

C2CD3 (HGNC:24564): (C2 domain containing 3 centriole elongation regulator) This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

C2CD3 Gene-Disease associations (from GenCC):

• orofaciodigital syndrome type 14

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen

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=0.14322704).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPME1	NM_016147.3	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 14	ENST00000328257.13	NP_057231.1
PPME1	NM_001271593.2	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 14		NP_001258522.1
PPME1	XM_047427116.1	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 12		XP_047283072.1
PPME1	XM_017017913.3	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 10		XP_016873402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPME1	ENST00000328257.13	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 14	1	NM_016147.3	ENSP00000329867.8
PPME1	ENST00000398427.6	c.27C>A	p.His9Gln	missense_variant	Exon 1 of 14	1		ENSP00000381461.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.27C>A (p.H9Q) alteration is located in exon 1 (coding exon 1) of the PPME1 gene. This alteration results from a C to A substitution at nucleotide position 27, causing the histidine (H) at amino acid position 9 to be replaced by a glutamine (Q). 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	0.17
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.95
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.67	T;T
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M
PhyloP100		-0.043
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.17
Sift	Benign	0.11	T;T
Sift4G	Benign	0.30	T;T
Polyphen		0.0	B;.
Vest4		0.31
MutPred		0.18		Gain of helix (P = 0.0199);Gain of helix (P = 0.0199);
MVP		0.33
MPC		0.44
ClinPred		0.34	T
GERP RS		3.1
PromoterAI		0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.45
Mutation Taster		=68/32	polymorphism

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

Other links and lift over

hg19: chr11-73882493;