11-10752676-T-C

Variant names:

• chr11-10752676-T-C
• NM_014633.5:c.50T>C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_014633.5(CTR9):​c.50T>C​(p.Ile17Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTR9 NM_014633.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 7.67

Genes affected

CTR9 (HGNC:16850): (CTR9 homolog, Paf1/RNA polymerase II complex component) The protein encoded by this gene is a component of the PAF1 complex, which associates with RNA polymerase II and functions in transcriptional regulation and elongation. This complex also plays a role in the modification of histones. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 11-10752676-T-C is Pathogenic according to our data. Variant chr11-10752676-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1173020.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTR9	NM_014633.5	c.50T>C	p.Ile17Thr	missense_variant	Exon 2 of 25	ENST00000361367.7	NP_055448.1
CTR9	NM_001346279.2	c.50T>C	p.Ile17Thr	missense_variant	Exon 2 of 24		NP_001333208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTR9	ENST00000361367.7	c.50T>C	p.Ile17Thr	missense_variant	Exon 2 of 25	1	NM_014633.5	ENSP00000355013.2
CTR9	ENST00000524523.1	c.11T>C	p.Ile4Thr	missense_variant	Exon 2 of 8	5		ENSP00000431458.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Mar 22, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35499524) -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CTR9: PM1, PM2, PP2, PS2:Supporting, PS4:Supporting -

CTR9-related neurodevelopmental disorder Uncertain:1

Apr 01, 2021

Centre of Medical Genetics, University of Antwerp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

PM2, PP3 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Uncertain	2.9	M;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.82
MutPred		0.69		Gain of disorder (P = 0.0097);.;
MVP		0.83
MPC		3.2
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.74
gMVP		0.52

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-10774223;