rs796052124

Positions:

• chr6-43517331-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_203290.4(POLR1C):​c.95A>T​(p.Asn32Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR1C NM_203290.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 6.38

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_203290.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-43517331-A-T is Pathogenic according to our data. Variant chr6-43517331-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 204588.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-43517331-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1C	NM_203290.4	c.95A>T	p.Asn32Ile	missense_variant	2/9	ENST00000642195.1
POLR1C	NM_001318876.2	c.95A>T	p.Asn32Ile	missense_variant	2/11
POLR1C	NM_001363658.2	c.95A>T	p.Asn32Ile	missense_variant	2/10
POLR1C	XM_047419577.1	c.95A>T	p.Asn32Ile	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1	c.95A>T	p.Asn32Ile	missense_variant	2/9		NM_203290.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 07, 2015	- -
Pathogenic, criteria provided, single submitter	research	MyeliNeuroGene Lab, McGill University Health Center Research Institute	-	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T;.;T;.;.;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;.;D;D;.;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.7	M;.;M;.;M;.;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.3	D;D;.;.;D;.;.;.
REVEL	Pathogenic	0.67
Sift	Benign	0.16	T;T;.;.;T;.;.;.
Sift4G	Benign	0.27	T;T;.;.;T;.;.;.
Polyphen		0.89	P;.;P;.;P;.;P;.
Vest4		0.95
MutPred		0.47		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);
MVP		0.84
MPC		0.16
ClinPred		0.98	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.60
gMVP		0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs796052124; hg19: chr6-43485069;