rs2231756

Positions:

• chr6-43517106-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_203290.4(POLR1C):​c.-4G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00543 in 1,614,146 control chromosomes in the GnomAD database, including 31 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 0.0038 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0056 (26 hom.)
• Consequence: POLR1C NM_203290.4 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.0180

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-43517106-G-A is Benign according to our data. Variant chr6-43517106-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 356868.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00376 (573/152342) while in subpopulation NFE AF= 0.00589 (401/68032). AF 95% confidence interval is 0.00542. There are 5 homozygotes in gnomad4. There are 263 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1C	NM_203290.4	c.-4G>A		5_prime_UTR_variant	1/9	ENST00000642195.1
POLR1C	NM_001318876.2	c.-4G>A		5_prime_UTR_variant	1/11
POLR1C	NM_001363658.2	c.-4G>A		5_prime_UTR_variant	1/10
POLR1C	XM_047419577.1	c.-4G>A		5_prime_UTR_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1	c.-4G>A		5_prime_UTR_variant	1/9		NM_203290.4	P1

Frequencies

GnomAD3 genomes AF: 0.00377 AC: 574 AN: 152224 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00589

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00444 AC: 1117 AN: 251488 Hom.: 2 AF XY: 0.00457 AC XY: 621 AN XY: 135920

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00374

Gnomad NFE exome AF: 0.00752

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00561 AC: 8197 AN: 1461804 Hom.: 26 Cov.: 31 AF XY: 0.00553 AC XY: 4019 AN XY: 727208

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00174

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.00666

Gnomad4 OTH exome AF: 0.00452

GnomAD4 genome AF: 0.00376 AC: 573 AN: 152342 Hom.: 5 Cov.: 32 AF XY: 0.00353 AC XY: 263 AN XY: 74488

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00339

Gnomad4 NFE AF: 0.00589

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00503 Hom.: 0

Bravo AF: 0.00345

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00496

EpiControl AF: 0.00593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Treacher Collins syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 19, 2016

- -

POLR1C-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 05, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2024

POLR1C: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	9.9
DANN	Benign	0.89

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: rs2231756; hg19: chr6-43484844;