chr6-43519384-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_203290.4(POLR1C):c.193A>G(p.Met65Val) variant causes a missense change. The variant allele was found at a frequency of 0.00146 in 1,614,026 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0015 ( 4 hom. )

Consequence

POLR1C
NM_203290.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:11O:1

Conservation

PhyloP100: 6.98

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:

ENSG00000271754 (HGNC:):

ENSG00000271754 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06145224).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000939 (143/152308) while in subpopulation NFE AF= 0.00171 (116/68020). AF 95% confidence interval is 0.00145. There are 0 homozygotes in gnomad4. There are 67 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1C	NM_203290.4 link	c.193A>G	p.Met65Val	missense_variant	Exon 3 of 9	ENST00000642195.1	NP_976035.1	O15160-1
POLR1C	NM_001318876.2 link	c.193A>G	p.Met65Val	missense_variant	Exon 3 of 9		NP_001305805.1	O15160-2
POLR1C	NM_001363658.2 link	c.193A>G	p.Met65Val	missense_variant	Exon 3 of 10		NP_001350587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1 link	c.193A>G	p.Met65Val	missense_variant	Exon 3 of 9		NM_203290.4	ENSP00000496044.1		O15160-1

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

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:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00171

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000851

AC:

214

AN:

251490

Hom.:

AF XY:

0.000853

AC XY:

116

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000924

Gnomad NFE exome

AF:

0.00152

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00151

AC:

2212

AN:

1461718

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

1069

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.00185

Gnomad4 OTH exome

AF:

0.00128

GnomAD4 genome

AF:

0.000939

AC:

143

AN:

152308

Hom.:

Cov.:

AF XY:

0.000900

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.00171

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00153

Hom.:

Bravo

AF:

0.000839

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00174

AC:

ExAC

AF:

0.000824

AC:

100

EpiCase

AF:

0.00202

EpiControl

AF:

0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:11Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 11

Pathogenic:1Uncertain:2Other:1

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 25, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: research

- -

not provided

Uncertain:3

Jan 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 65 of the POLR1C protein (p.Met65Val). This variant is present in population databases (rs141471029, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with POLR1C-related conditions (PMID: 26151409, 32042905, 33804237). ClinVar contains an entry for this variant (Variation ID: 356872). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POLR1C protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Aug 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26151409, 34426522, 33804237, 32042905) -

not specified

Uncertain:2

May 28, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLR1C c.193A>G (p.Met65Val) results in a conservative amino acid change located in the DNA-directed RNA polymerase, RpoA/D/Rpb3-type (IPR011263) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 1614026 control chromosomes in the gnomAD database, including 4 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in POLR1C causing POLR1C-Related Disorders, however published literature suggests biallelic individuals are expected to have early onset severe disease incompatible with homozygous controls. c.193A>G has been reported in the literature in the presumed or confirmed compound heterozygous state at least 4 individuals affected with clinical features of Hypomyelinating Leukodystrophy (example, Thiffault_2015, Gauquelin_2019, Ching-Lopez_2021, Schluter_2022), including at least 1 individual who carried a pathogenic variant in trans. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33804237, 32042905, 35012964, 26151409). ClinVar contains an entry for this variant (Variation ID: 356872). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Nov 28, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193A>G (p.M65V) alteration is located in exon 3 (coding exon 3) of the POLR1C gene. This alteration results from a A to G substitution at nucleotide position 193, causing the methionine (M) at amino acid position 65 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

POLR1C-related disorder

Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.193A>G (p.Met65Val) variant has been reported in one study in which it is found in a compound heterozygous state with another missense variant in an individual with a clinical phenotype of leukodystrophy, hypomyelinating (Thiffault et al. 2015). Control data are unavailable for this variant, which is reported at a frequency of 0.00174 in the European American population of the Exome Sequencing Project. The evidence for this variant is limited. The p.Met65Val variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for POLR1C-related disorders. -

Hearing impairment

Uncertain:1

Apr 12, 2021

Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS1_Strong, PP3_Supporting, BS1_Supporting -

Treacher Collins syndrome 3;C4225305:Hypomyelinating leukodystrophy 11

Uncertain:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

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

Eigen

Benign

0.073

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.082

MetaRNN

Benign

0.061

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.1

.;.;L;.;L;.;L;.;L;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.4

N;.;N;N;.;.;N;.;.;.

REVEL

Uncertain

0.58

Sift

Benign

0.030

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

Sift4G

Benign

0.095

T;.;T;T;.;.;T;.;.;.

Polyphen

0.067, 0.046

.;.;B;.;B;.;B;.;B;.

Vest4

0.93, 0.86, 0.94

MVP

0.78

MPC

0.13

ClinPred

0.033

GERP RS

5.1

Varity_R

0.77

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