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rs3212986

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_012099.3(POLR1G):c.1510C>A(p.Gln504Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 1,605,796 control chromosomes in the GnomAD database, including 54,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.27 ( 5761 hom., cov: 31)
Exomes 𝑓: 0.26 ( 48450 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

18

Clinical Significance

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

Conservation

PhyloP100: -1.51
Variant links:
Genes affected
POLR1G (HGNC:24219): (RNA polymerase I subunit G) Enables RNA binding activity. Predicted to be involved in transmembrane receptor protein tyrosine kinase signaling pathway. Predicted to act upstream of or within rRNA transcription. Located in cytosol; mitochondrion; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]
ERCC1 (HGNC:3433): (ERCC excision repair 1, endonuclease non-catalytic subunit) The product of this gene functions in the nucleotide excision repair pathway, and is required for the repair of DNA lesions such as those induced by UV light or formed by electrophilic compounds including cisplatin. The encoded protein forms a heterodimer with the XPF endonuclease (also known as ERCC4), and the heterodimeric endonuclease catalyzes the 5' incision in the process of excising the DNA lesion. The heterodimeric endonuclease is also involved in recombinational DNA repair and in the repair of inter-strand crosslinks. Mutations in this gene result in cerebrooculofacioskeletal syndrome, and polymorphisms that alter expression of this gene may play a role in carcinogenesis. Multiple transcript variants encoding different isoforms have been found for this gene. The last exon of this gene overlaps with the CD3e molecule, epsilon associated protein gene on the opposite strand. [provided by RefSeq, Oct 2009]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=6.0486794E-4).
BP6
Variant 19-45409478-C-A is Benign according to our data. Variant chr19-45409478-C-A is described in ClinVar as [Benign]. Clinvar id is 225987.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
POLR1GNM_012099.3 linkuse as main transcriptc.1510C>A p.Gln504Lys missense_variant 3/3 ENST00000309424.8
ERCC1NM_001983.4 linkuse as main transcriptc.*197G>T 3_prime_UTR_variant 10/10 ENST00000300853.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
POLR1GENST00000309424.8 linkuse as main transcriptc.1510C>A p.Gln504Lys missense_variant 3/31 NM_012099.3 P4O15446-1
ERCC1ENST00000300853.8 linkuse as main transcriptc.*197G>T 3_prime_UTR_variant 10/101 NM_001983.4 P1P07992-1

Frequencies

GnomAD3 genomes
AF:
0.272
AC:
41313
AN:
151910
Hom.:
5750
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.294
Gnomad AMI
AF:
0.354
Gnomad AMR
AF:
0.351
Gnomad ASJ
AF:
0.245
Gnomad EAS
AF:
0.309
Gnomad SAS
AF:
0.303
Gnomad FIN
AF:
0.225
Gnomad MID
AF:
0.213
Gnomad NFE
AF:
0.244
Gnomad OTH
AF:
0.267
GnomAD3 exomes
AF:
0.289
AC:
67411
AN:
233160
Hom.:
9838
AF XY:
0.284
AC XY:
36050
AN XY:
127022
show subpopulations
Gnomad AFR exome
AF:
0.307
Gnomad AMR exome
AF:
0.419
Gnomad ASJ exome
AF:
0.257
Gnomad EAS exome
AF:
0.322
Gnomad SAS exome
AF:
0.304
Gnomad FIN exome
AF:
0.225
Gnomad NFE exome
AF:
0.251
Gnomad OTH exome
AF:
0.269
GnomAD4 exome
AF:
0.256
AC:
371853
AN:
1453768
Hom.:
48450
Cov.:
40
AF XY:
0.256
AC XY:
184992
AN XY:
722782
show subpopulations
Gnomad4 AFR exome
AF:
0.285
Gnomad4 AMR exome
AF:
0.407
Gnomad4 ASJ exome
AF:
0.245
Gnomad4 EAS exome
AF:
0.270
Gnomad4 SAS exome
AF:
0.303
Gnomad4 FIN exome
AF:
0.221
Gnomad4 NFE exome
AF:
0.246
Gnomad4 OTH exome
AF:
0.266
GnomAD4 genome
AF:
0.272
AC:
41356
AN:
152028
Hom.:
5761
Cov.:
31
AF XY:
0.273
AC XY:
20304
AN XY:
74314
show subpopulations
Gnomad4 AFR
AF:
0.293
Gnomad4 AMR
AF:
0.352
Gnomad4 ASJ
AF:
0.245
Gnomad4 EAS
AF:
0.310
Gnomad4 SAS
AF:
0.303
Gnomad4 FIN
AF:
0.225
Gnomad4 NFE
AF:
0.244
Gnomad4 OTH
AF:
0.271
Alfa
AF:
0.254
Hom.:
11489
Bravo
AF:
0.284
TwinsUK
AF:
0.260
AC:
965
ALSPAC
AF:
0.249
AC:
961
ESP6500AA
AF:
0.291
AC:
1274
ESP6500EA
AF:
0.246
AC:
2109
ExAC
AF:
0.271
AC:
32582
Asia WGS
AF:
0.315
AC:
1096
AN:
3478

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeJan 30, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxNov 11, 2018This variant is associated with the following publications: (PMID: 10952103, 18635523, 23203453) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.059
BayesDel_addAF
Benign
-0.87
T
BayesDel_noAF
Benign
-0.88
Cadd
Benign
0.0080
Dann
Benign
0.53
DEOGEN2
Benign
0.0031
T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.7
FATHMM_MKL
Benign
0.0092
N
LIST_S2
Benign
0.26
T;T
MetaRNN
Benign
0.00060
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
-1.6
N;.
MutationTaster
Benign
1.0
P;P;P;P
PrimateAI
Benign
0.32
T
PROVEAN
Benign
1.4
N;.
REVEL
Benign
0.028
Sift
Benign
1.0
T;.
Sift4G
Benign
0.33
T;T
Polyphen
0.0
B;B
Vest4
0.058
MPC
0.19
ClinPred
0.0026
T
GERP RS
2.7
Varity_R
0.045
gMVP
0.043

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.

Other links and lift over

dbSNP: rs3212986; hg19: chr19-45912736; COSMIC: COSV50003942; COSMIC: COSV50003942; API