NM_203290.4:c.-4G>A

Variant names:

• chr6-43517106-G-A
• rs2231756
• NM_203290.4:c.-4G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 1 publications found

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]

YIPF3 (HGNC:21023): (Yip1 domain family member 3) Predicted to be involved in cell differentiation. Located in Golgi apparatus and transport vesicle. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -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 CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 356868. Variant chr6-43517106-G-A is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 356868.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1C	NM_203290.4	c.-4G>A		5_prime_UTR_variant	Exon 1 of 9	ENST00000642195.1	NP_976035.1
YIPF3	NM_015388.4	c.-299C>T		upstream_gene_variant		ENST00000372422.7	NP_056203.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1	c.-4G>A		5_prime_UTR_variant	Exon 1 of 9		NM_203290.4	ENSP00000496044.1
YIPF3	ENST00000372422.7	c.-299C>T		upstream_gene_variant		1	NM_015388.4	ENSP00000361499.2

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

GnomAD2 exomes AF: 0.00444 AC: 1117 AN: 251488 AF XY: 0.00457

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 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

African (AFR) AF: 0.00105 AC: 35 AN: 33480

American (AMR) AF: 0.00253 AC: 113 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00174 AC: 150 AN: 86256

European-Finnish (FIN) AF: 0.00402 AC: 215 AN: 53418

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5766

European-Non Finnish (NFE) AF: 0.00666 AC: 7401 AN: 1111930

Other (OTH) AF: 0.00452 AC: 273 AN: 60394

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

African (AFR) AF: 0.00132 AC: 55 AN: 41578

American (AMR) AF: 0.00457 AC: 70 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00339 AC: 36 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00589 AC: 401 AN: 68032

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

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

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Feb 19, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

POLR1C-related disorder Benign:1

Nov 05, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.018
PromoterAI		0.12	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs2231756; hg19: chr6-43484844;