rs796052126

Positions:

• chr6-43517313-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• 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]

ACMG classification

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

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:3 Other: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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M;.;M;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	N;N;.;.;D;.;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D;D;.;.;D;.;.;.
Sift4G	Uncertain	0.0050	D;D;.;.;D;.;.;.
Polyphen		0.99	D;.;D;.;D;.;D;.
Vest4		0.94
MutPred		0.41		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		0.92
MPC		0.12
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.54
gMVP		0.82

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

LitVar

Other links and lift over

dbSNP: rs796052126; hg19: chr6-43485051;