rs796052126

Variant names:

• chr6-43517313-C-T
• rs796052126
• NM_203290.4:c.77C>T

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_203290.4(POLR1C):​c.77C>T​(p.Thr26Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 6.88
• Publications: 7 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: Pathogenic. The variant received 13 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, 8 uncertain in NM_203290.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• PP5: Variant 6-43517313-C-T is Pathogenic according to our data. Variant chr6-43517313-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 204591.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.77C>T	p.Thr26Ile	missense	Exon 2 of 9	NP_976035.1	O15160-1
	POLR1C	NM_001318876.2		c.77C>T	p.Thr26Ile	missense	Exon 2 of 9	NP_001305805.1	O15160-2
	POLR1C	NM_001363658.2		c.77C>T	p.Thr26Ile	missense	Exon 2 of 10	NP_001350587.1	A0A2R8YEZ4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1C	ENST00000642195.1	MANE Select	c.77C>T	p.Thr26Ile	missense	Exon 2 of 9	ENSP00000496044.1	O15160-1
	POLR1C	ENST00000304004.7	TSL:1	c.77C>T	p.Thr26Ile	missense	Exon 2 of 9	ENSP00000307212.3	O15160-2
	POLR1C	ENST00000945270.1		c.77C>T	p.Thr26Ile	missense	Exon 2 of 9	ENSP00000615329.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hypomyelinating leukodystrophy 11 (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.50	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		6.9
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	N
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.99	D
Vest4		0.94
MutPred		0.41		Gain of sheet (P = 0.0344)
MVP		0.92
MPC		0.12
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		0.022	Neutral
Varity_R		0.54
gMVP		0.82
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs796052126; hg19: chr6-43485051;