11-10751456-A-G

Position:

• chr11-10751456-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PM5 PP2 PP3_Moderate PP5_Moderate

The NM_014633.5(CTR9):​c.44A>G​(p.Glu15Gly) variant causes a missense, splice region 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. 13/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E15K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTR9 NM_014633.5 missense, splice_region
• Scores: Splicing: ADA: 0.9945
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.48

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-10751455-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1173018.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, CTR9
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.892
• PP5: Variant 11-10751456-A-G is Pathogenic according to our data. Variant chr11-10751456-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3078716.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTR9	NM_014633.5	c.44A>G	p.Glu15Gly	missense_variant, splice_region_variant	1/25	ENST00000361367.7
CTR9	NM_001346279.2	c.44A>G	p.Glu15Gly	missense_variant, splice_region_variant	1/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTR9	ENST00000361367.7	c.44A>G	p.Glu15Gly	missense_variant, splice_region_variant	1/25	1	NM_014633.5	P1
CTR9	ENST00000524523.1	c.5A>G	p.Glu2Gly	missense_variant, splice_region_variant	1/8	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 23, 2024

The c.44A>G (p.E15G) alteration is located in exon 1 (coding exon 1) of the CTR9 gene. This alteration results from an A to G substitution at nucleotide position 44, causing the glutamic acid (E) at amino acid position 15 to be replaced by a glycine (G). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Two other alterations at the same codon, c.43G>A (p.E15K) and c.45G>C (p.E15D), have been determined to be the result of a de novo mutation in individuals with features consistent with CTR9-related neurodevelopmental disorder (Meuwissen, 2022; Suzuki, 2022). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek, 2016; Firth, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Pathogenic	3.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.8	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.96	D;.
Vest4		0.79
MutPred		0.75		Loss of disorder (P = 0.081);.;
MVP		0.88
MPC		3.3
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.83
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.88
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: chr11-10773003; COSMIC: COSV63729557;