rs796052126
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong
The NM_203290.4(POLR1C):c.77C>T(p.Thr26Ile) variant causes a missense change. 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 Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
POLR1C
NM_203290.4 missense
NM_203290.4 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 6.88
Genes affected
POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 13 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_203290.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.825
PP5
?
Variant 6-43517313-C-T is Pathogenic according to our data. Variant chr6-43517313-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 204591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43517313-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
POLR1C | NM_203290.4 | c.77C>T | p.Thr26Ile | missense_variant | 2/9 | ENST00000642195.1 | |
POLR1C | NM_001318876.2 | c.77C>T | p.Thr26Ile | missense_variant | 2/11 | ||
POLR1C | NM_001363658.2 | c.77C>T | p.Thr26Ile | missense_variant | 2/10 | ||
POLR1C | XM_047419577.1 | c.77C>T | p.Thr26Ile | missense_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
POLR1C | ENST00000642195.1 | c.77C>T | p.Thr26Ile | missense_variant | 2/9 | NM_203290.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hypomyelinating leukodystrophy 11 Pathogenic:3Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense variant c.77C>T (p.Thr26Ile) in POLR1C gene has been reported in affected individuals in the literature (Thiffault I et.al.,2015). This variant has been reported to the ClinVar database as Pathogenic. The p.Thr26Ile variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Thr at position 26 is changed to a Ile changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Thr26Ile in POLR1C is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic . - |
Pathogenic, criteria provided, single submitter | research | MyeliNeuroGene Lab, McGill University Health Center Research Institute | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 07, 2015 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M;.;M;.;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
N;N;.;.;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;.;.;D;.;.;.
Sift4G
Uncertain
D;D;.;.;D;.;.;.
Polyphen
D;.;D;.;D;.;D;.
Vest4
MutPred
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at