rs141156009

Positions:

chr6-43520961-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_203290.4(POLR1C):c.835C>T(p.Arg279Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000421 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R279Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

POLR1C
NM_203290.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.02

Variant links:

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]

POLR1C links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a helix (size 2) in uniprot entity RPAC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_203290.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-43520962-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.928

PP5

Variant 6-43520961-C-T is Pathogenic according to our data. Variant chr6-43520961-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-43520961-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
POLR1C	NM_203290.4 linkuse as main transcript	c.835C>T	p.Arg279Trp	missense_variant	8/9	ENST00000642195.1
POLR1C	NM_001318876.2 linkuse as main transcript	c.835C>T	p.Arg279Trp	missense_variant	8/11
POLR1C	NM_001363658.2 linkuse as main transcript	c.835C>T	p.Arg279Trp	missense_variant	8/10
POLR1C	XM_047419577.1 linkuse as main transcript	c.835C>T	p.Arg279Trp	missense_variant	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1 linkuse as main transcript	c.835C>T	p.Arg279Trp	missense_variant	8/9		NM_203290.4	P1	O15160-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000437

AC:

AN:

251432

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000390

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000161

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 27, 2016

The R279W variant in the POLR1C gene has been reported previously in an individual with Treacher Collinssyndrome who was compound heterozygous for the R279W variant and a truncating variant (Dauwerse et al., 2011).The R279W variant was not observed with any significant frequency in approximately 6500 individuals of Europeanand African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benignvariant in these populations. The R279W variant is a non-conservative amino acid substitution, which occurs at aposition that is conserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. The functional importance of the R279 residue is supported by the presence of a different missensevariant (R279Q) reported in two affected siblings with TCS who harbored another POLR1C variant (phase notconfirmed), as well as in an unrelated individual with TCS who was compound heterozygous for R279Q and anonsense variant in POLR1C (Dauwerse et al., 2011). Therefore, we interpret R279W as a pathogenic variant. -

Treacher Collins syndrome 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2011

- -

Hypomyelinating leukodystrophy 11

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

MyeliNeuroGene Lab, McGill University Health Center Research Institute

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.79

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.90

.;D;.;D;.;.;.;.;.

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

D;.;.;D;D;.;D;D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Pathogenic

3.5

.;H;.;H;.;H;.;H;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.0

.;D;D;.;.;D;.;.;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0030

.;D;D;.;.;D;.;.;.

Sift4G

Uncertain

0.0030

.;D;D;.;.;D;.;.;.

Polyphen

1.0

.;D;.;D;.;D;.;D;.

Vest4

0.92, 0.84, 0.94

MVP

0.94

MPC

0.47

ClinPred

0.84

GERP RS

2.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.77

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over