rs141471029

Positions:

• chr6-43519384-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM1 BP4_Strong BS1_Supporting BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:10 O:1
• Conservation: PhyloP100: 6.98

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_203290.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.06145224).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00151 (2212/1461718) while in subpopulation NFE AF= 0.00185 (2059/1111860). AF 95% confidence interval is 0.00178. There are 4 homozygotes in gnomad4_exome. There are 1069 alleles in male gnomad4_exome subpopulation. Median coverage is 30. 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/exons	MANE	UniProt
POLR1C	NM_203290.4	c.193A>G	p.Met65Val	missense_variant	3/9	ENST00000642195.1
POLR1C	NM_001318876.2	c.193A>G	p.Met65Val	missense_variant	3/11
POLR1C	NM_001363658.2	c.193A>G	p.Met65Val	missense_variant	3/10
POLR1C	XM_047419577.1	c.193A>G	p.Met65Val	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1	c.193A>G	p.Met65Val	missense_variant	3/9		NM_203290.4	P1
	ENST00000607571.1	n.341T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152190 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.000853 AC XY: 116 AN XY: 135920

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.: 4 Cov.: 30 AF XY: 0.00147 AC XY: 1069 AN XY: 727182

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.: 0 Cov.: 32 AF XY: 0.000900 AC XY: 67 AN XY: 74472

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.: 0

Bravo AF: 0.000839

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00174 AC: 15

ExAC AF: 0.000824 AC: 100

EpiCase AF: 0.00202

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:10 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:1 Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 05, 2017	The POLR1C c.193A>G (p.Met65Val) missense 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 hypomyelinating leukodystrophy (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 Pol III-related leukodystrophy. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	MyeliNeuroGene Lab, McGill University Health Center Research Institute	-	- -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2023	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

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 28, 2017	- -

POLR1C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 21, 2021

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. -

Hearing impairment Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 12, 2021

PS1_Strong, PP3_Supporting, BS1_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
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	D
LIST_S2	Uncertain	0.97	D;D;.;.;D;D;.;D;D;D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.061	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Benign	1.1	.;.;L;.;L;.;L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
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	T
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

Other links and lift over

dbSNP: rs141471029; hg19: chr6-43487122;