Variant chr13-27622945-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_015972.4(POLR1D):c.97G>C(p.Ala33Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,506 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POLR1D
NM_015972.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.62

Variant links:

Genes affected

POLR1D (HGNC:20422): (RNA polymerase I and III subunit D) The protein encoded by this gene is a component of the RNA polymerase I and RNA polymerase III complexes, which function in the synthesis of ribosomal RNA precursors and small RNAs, respectively. Mutations in this gene are a cause of Treacher Collins syndrome (TCS), a craniofacial development disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

POLR1D links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM1

In a chain DNA-directed RNA polymerases I and III subunit RPAC2 (size 132) in uniprot entity RPAC2_HUMAN there are 18 pathogenic changes around while only 2 benign (90%) in NM_015972.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32556337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1D	NM_015972.4 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/2	ENST00000302979.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1D	ENST00000302979.5 linkuse as main transcript	c.97G>C	p.Ala33Pro	missense_variant	2/2	1	NM_015972.4	P1	P0DPB6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251464

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726676

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The c.97G>C (p.A33P) alteration is located in exon 2 (coding exon 2) of the POLR1D gene. This alteration results from a G to C substitution at nucleotide position 97, causing the alanine (A) at amino acid position 33 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Uncertain

-0.050

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

.;.;T

Eigen

Benign

-0.084

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.052

MetaRNN

Benign

0.33

T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

0.55

N;N;.

MutationTaster

Benign

0.82

D;D;D

PROVEAN

Benign

-1.2

N;.;.

REVEL

Uncertain

0.29

Sift

Benign

0.37

T;.;.

Sift4G

Benign

0.25

T;.;T

Vest4

0.22

MutPred

0.54

Gain of catalytic residue at R37 (P = 0.0028);Gain of catalytic residue at R37 (P = 0.0028);.;

MVP

0.96

MPC

0.29

ClinPred

0.51

GERP RS

4.1

Varity_R

0.23

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over