NM_203290.4:c.141+168C>T

Variant names:

• chr6-43517545-C-T
• rs2227301
• NM_203290.4:c.141+168C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_203290.4(POLR1C):​c.141+168C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 151,750 control chromosomes in the GnomAD database, including 3,105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.18 (3105 hom., cov: 31)
• Consequence: POLR1C NM_203290.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.761
• Publications: 11 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]

POLR1C Gene-Disease associations (from GenCC):

• hypomyelinating leukodystrophy 11

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Treacher Collins syndrome 3

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen
• Treacher-Collins syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hypomyelination-hypogonadotropic hypogonadism-hypodontia syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-43517545-C-T is Benign according to our data. Variant chr6-43517545-C-T is described in ClinVar as Benign. ClinVar VariationId is 1277590.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203290.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1C	NM_203290.4	MANE Select	c.141+168C>T		intron	N/A	NP_976035.1	O15160-1
	POLR1C	NM_001318876.2		c.141+168C>T		intron	N/A	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.141+168C>T		intron	N/A	NP_001350587.1	A0A2R8YEZ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1C	ENST00000642195.1	MANE Select	c.141+168C>T		intron	N/A	ENSP00000496044.1	O15160-1
	POLR1C	ENST00000304004.7	TSL:1	c.141+168C>T		intron	N/A	ENSP00000307212.3	O15160-2
	POLR1C	ENST00000945270.1		c.141+168C>T		intron	N/A	ENSP00000615329.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27014 AN: 151630 Hom.: 3100 Cov.: 31

Gnomad AFR AF: 0.0512

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.156

Gnomad EAS AF: 0.0272

Gnomad SAS AF: 0.245

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.233

Gnomad OTH AF: 0.174

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 27019 AN: 151750 Hom.: 3105 Cov.: 31 AF XY: 0.183 AC XY: 13561 AN XY: 74104

African (AFR) AF: 0.0510 AC: 2110 AN: 41374

American (AMR) AF: 0.232 AC: 3539 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 542 AN: 3466

East Asian (EAS) AF: 0.0273 AC: 141 AN: 5164

South Asian (SAS) AF: 0.245 AC: 1171 AN: 4780

European-Finnish (FIN) AF: 0.284 AC: 2981 AN: 10500

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.233 AC: 15797 AN: 67918

Other (OTH) AF: 0.171 AC: 360 AN: 2110

Alfa AF: 0.222 Hom.: 2084

Bravo AF: 0.166

Asia WGS AF: 0.117 AC: 406 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.9
DANN	Benign	0.83
PhyloP100		-0.76
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs2227301; hg19: chr6-43485283;