rs371802902

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_203290.4(POLR1C):c.221A>G(p.Asn74Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

POLR1C
NM_203290.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:1

Conservation

PhyloP100: 8.83

Publications

14 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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

POLR1C links:

ENSG00000271754 (HGNC:):

ENSG00000271754 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.922

PP5

Variant 6-43519412-A-G is Pathogenic according to our data. Variant chr6-43519412-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 204587.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1C	NM_203290.4 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 3 of 9	ENST00000642195.1	NP_976035.1	O15160-1
POLR1C	NM_001318876.2 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 3 of 9		NP_001305805.1	O15160-2
POLR1C	NM_001363658.2 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 3 of 10		NP_001350587.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1C	ENST00000642195.1 link	c.221A>G	p.Asn74Ser	missense_variant	Exon 3 of 9		NM_203290.4	ENSP00000496044.1		O15160-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251474

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111574

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0000724

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypomyelinating leukodystrophy 11

Pathogenic:4Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

MyeliNeuroGene Lab, McGill University Health Center Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 07, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 18, 2023

3billion

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). Predicted Consequence/Location: Missense variant Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 26151409). In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.92 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.96 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000204587 /PMID: 26151409). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 26151409). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

not provided

Uncertain:1

Sep 12, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects POLR1C function (PMID: 30505682). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POLR1C protein function. ClinVar contains an entry for this variant (Variation ID: 204587). This missense change has been observed in individual(s) with POLR1C-related conditions (PMID: 26151409, 33804237). This variant is present in population databases (rs371802902, gnomAD 0.02%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 74 of the POLR1C protein (p.Asn74Ser). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.054

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.;D;.;D;.;.;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D;.;.;D;D;.;D;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

.;.;M;.;M;.;M;.;M;.

PhyloP100

8.8

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.0

D;.;D;D;.;.;D;.;.;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0020

D;.;D;D;.;.;D;.;.;.

Sift4G

Uncertain

0.0020

D;.;D;D;.;.;D;.;.;.

Polyphen

1.0, 1.0

.;.;D;.;D;.;D;.;D;.

Vest4

0.98, 0.97, 0.99

MVP

0.91

MPC

0.42

ClinPred

0.91

GERP RS

5.3

Varity_R

0.93

gMVP

0.93

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over