19-45408744-A-C

Position:

chr19-45408744-A-C

Variant summary

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

The NM_012099.3(POLR1G):c.776A>C(p.Lys259Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,613,634 control chromosomes in the GnomAD database, including 26,721 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.20 ( 3539 hom., cov: 31)

Exomes 𝑓: 0.16 ( 23182 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.0620

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]

POLR1G links:

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]

ERCC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.5674057E-4).

BP6

Variant 19-45408744-A-C is Benign according to our data. Variant chr19-45408744-A-C is described in ClinVar as [Benign]. Clinvar id is 1248262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.427 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3 linkuse as main transcript	c.776A>C	p.Lys259Thr	missense_variant	3/3	ENST00000309424.8	NP_036231.1	O15446-1
ERCC1	NM_001983.4 linkuse as main transcript	c.*931T>G		3_prime_UTR_variant	10/10	ENST00000300853.8	NP_001974.1	P07992-1A0A024R0Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8 linkuse as main transcript	c.776A>C	p.Lys259Thr	missense_variant	3/3	1	NM_012099.3	ENSP00000310966.3		O15446-1
ERCC1	ENST00000300853 linkuse as main transcript	c.*931T>G		3_prime_UTR_variant	10/10	1	NM_001983.4	ENSP00000300853.3		P07992-1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30488

AN:

151718

Hom.:

3535

Cov.:

show subpopulations

Gnomad AFR

AF:

0.282

Gnomad AMI

AF:

0.124

Gnomad AMR

AF:

0.210

Gnomad ASJ

AF:

0.137

Gnomad EAS

AF:

0.443

Gnomad SAS

AF:

0.272

Gnomad FIN

AF:

0.144

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.139

Gnomad OTH

AF:

0.199

GnomAD3 exomes

AF:

0.208

AC:

51762

AN:

248372

Hom.:

6477

AF XY:

0.204

AC XY:

27436

AN XY:

134672

show subpopulations

Gnomad AFR exome

AF:

0.288

Gnomad AMR exome

AF:

0.274

Gnomad ASJ exome

AF:

0.141

Gnomad EAS exome

AF:

0.437

Gnomad SAS exome

AF:

0.263

Gnomad FIN exome

AF:

0.158

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.177

GnomAD4 exome

AF:

0.164

AC:

240266

AN:

1461798

Hom.:

23182

Cov.:

AF XY:

0.167

AC XY:

121295

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.287

Gnomad4 AMR exome

AF:

0.265

Gnomad4 ASJ exome

AF:

0.140

Gnomad4 EAS exome

AF:

0.461

Gnomad4 SAS exome

AF:

0.263

Gnomad4 FIN exome

AF:

0.158

Gnomad4 NFE exome

AF:

0.139

Gnomad4 OTH exome

AF:

0.176

GnomAD4 genome

AF:

0.201

AC:

30519

AN:

151836

Hom.:

3539

Cov.:

AF XY:

0.204

AC XY:

15178

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.282

Gnomad4 AMR

AF:

0.210

Gnomad4 ASJ

AF:

0.137

Gnomad4 EAS

AF:

0.443

Gnomad4 SAS

AF:

0.271

Gnomad4 FIN

AF:

0.144

Gnomad4 NFE

AF:

0.139

Gnomad4 OTH

AF:

0.198

Alfa

AF:

0.154

Hom.:

3133

Bravo

AF:

0.208

TwinsUK

AF:

0.143

AC:

532

ALSPAC

AF:

0.146

AC:

564

ESP6500AA

AF:

0.271

AC:

1193

ESP6500EA

AF:

0.135

AC:

1160

ExAC

AF:

0.208

AC:

25221

Asia WGS

AF:

0.339

AC:

1176

AN:

3478

EpiCase

AF:

0.142

EpiControl

AF:

0.139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	This variant is associated with the following publications: (PMID: 24140460, 23775331) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.046

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.83

CADD

Benign

DANN

Benign

0.76

DEOGEN2

Benign

0.0095

T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0057

LIST_S2

Benign

0.14

T;T

MetaRNN

Benign

0.00076

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.90

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

0.070

N;.

REVEL

Benign

0.028

Sift

Benign

0.71

T;.

Sift4G

Benign

0.57

T;T

Polyphen

0.0

B;B

Vest4

0.088

MPC

0.17

ClinPred

0.00052

GERP RS

-1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.044

gMVP

0.035

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