2-112551896-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_019014.6(POLR1B):c.884C>T(p.Ser295Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.558 in 1,613,374 control chromosomes in the GnomAD database, including 255,197 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20439 hom., cov: 32)

Exomes 𝑓: 0.56 ( 234758 hom. )

Consequence

POLR1B
NM_019014.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0840

Publications

35 publications found

Variant links:

Genes affected

POLR1B (HGNC:20454): (RNA polymerase I subunit B) Eukaryotic RNA polymerase I (pol I) is responsible for the transcription of ribosomal RNA (rRNA) genes and production of rRNA, the primary component of ribosomes. Pol I is a multisubunit enzyme composed of 6 to 14 polypeptides, depending on the species. Most of the mass of the pol I complex derives from the 2 largest subunits, Rpa1 and Rpa2 in yeast. POLR1B is homologous to Rpa2 (Seither and Grummt, 1996 [PubMed 8921381]).[supplied by OMIM, Mar 2008]

POLR1B Gene-Disease associations (from GenCC):

Treacher Collins syndrome 4
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
Treacher-Collins syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POLR1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=3.0312503E-6).

BP6

Variant 2-112551896-C-T is Benign according to our data. Variant chr2-112551896-C-T is described in ClinVar as Benign. ClinVar VariationId is 1260138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.581 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1B	NM_019014.6 link	c.884C>T	p.Ser295Leu	missense_variant	Exon 6 of 15	ENST00000263331.10	NP_061887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1B	ENST00000263331.10 link	c.884C>T	p.Ser295Leu	missense_variant	Exon 6 of 15	2	NM_019014.6	ENSP00000263331.5

Frequencies

GnomAD3 genomes

AF:

0.512

AC:

77666

AN:

151834

Hom.:

20427

Cov.:

show subpopulations

Gnomad AFR

AF:

0.412

Gnomad AMI

AF:

0.485

Gnomad AMR

AF:

0.497

Gnomad ASJ

AF:

0.622

Gnomad EAS

AF:

0.364

Gnomad SAS

AF:

0.496

Gnomad FIN

AF:

0.478

Gnomad MID

AF:

0.639

Gnomad NFE

AF:

0.586

Gnomad OTH

AF:

0.554

GnomAD2 exomes

AF:

0.522

AC:

131281

AN:

251460

AF XY:

0.528

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.461

Gnomad ASJ exome

AF:

0.622

Gnomad EAS exome

AF:

0.350

Gnomad FIN exome

AF:

0.483

Gnomad NFE exome

AF:

0.587

Gnomad OTH exome

AF:

0.556

GnomAD4 exome

AF:

0.563

AC:

822793

AN:

1461422

Hom.:

234758

Cov.:

AF XY:

0.563

AC XY:

409138

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.412

AC:

13781

AN:

33468

American (AMR)

AF:

0.468

AC:

20925

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.619

AC:

16165

AN:

26128

East Asian (EAS)

AF:

0.340

AC:

13498

AN:

39698

South Asian (SAS)

AF:

0.502

AC:

43333

AN:

86246

European-Finnish (FIN)

AF:

0.481

AC:

25691

AN:

53418

Middle Eastern (MID)

AF:

0.631

AC:

3638

AN:

5766

European-Non Finnish (NFE)

AF:

0.587

AC:

652763

AN:

1111600

Other (OTH)

AF:

0.547

AC:

32999

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

18932

37864

56797

75729

94661

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17812

35624

53436

71248

89060

<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:

0.511

AC:

77709

AN:

151952

Hom.:

20439

Cov.:

AF XY:

0.505

AC XY:

37475

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.412

AC:

17062

AN:

41408

American (AMR)

AF:

0.497

AC:

7588

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.622

AC:

2157

AN:

3470

East Asian (EAS)

AF:

0.362

AC:

1870

AN:

5164

South Asian (SAS)

AF:

0.495

AC:

2381

AN:

4814

European-Finnish (FIN)

AF:

0.478

AC:

5040

AN:

10548

Middle Eastern (MID)

AF:

0.646

AC:

190

AN:

294

European-Non Finnish (NFE)

AF:

0.586

AC:

39810

AN:

67962

Other (OTH)

AF:

0.556

AC:

1172

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1900

3800

5701

7601

9501

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

694

1388

2082

2776

3470

<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:

0.559

Hom.:

110420

Bravo

AF:

0.509

TwinsUK

AF:

0.584

AC:

2165

ALSPAC

AF:

0.574

AC:

2213

ESP6500AA

AF:

0.417

AC:

1838

ESP6500EA

AF:

0.596

AC:

5129

ExAC

AF:

0.523

AC:

63474

Asia WGS

AF:

0.446

AC:

1550

AN:

3478

EpiCase

AF:

0.588

EpiControl

AF:

0.599

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.14

T;.;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.093

LIST_S2

Benign

0.46

T;T;T;T;T

MetaRNN

Benign

0.0000030

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.090

N;.;.;N;.

PhyloP100

-0.084

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.39

N;N;N;N;N

REVEL

Benign

0.016

Sift

Benign

0.36

T;T;T;T;T

Sift4G

Benign

0.63

T;T;T;T;T

Polyphen

0.0

B;.;.;.;B

Vest4

0.042

MPC

0.19

ClinPred

0.0081

GERP RS

-2.6

Varity_R

0.025

gMVP

0.28

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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