rs3212986

chr19-45409478-C-Achr19-45409478-C-Gchr19-45409478-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 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 0.27 (5761 hom., cov: 31)
  • Exomes 𝑓: 0.26 (48450 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.51

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]

ACMG classification

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
POLR1G	NM_012099.3	c.1510C>A	p.Gln504Lys	missense_variant	3/3	ENST00000309424.8
ERCC1	NM_001983.4	c.*197G>T		3_prime_UTR_variant	10/10	ENST00000300853.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1G	ENST00000309424.8	c.1510C>A	p.Gln504Lys	missense_variant	3/3	1	NM_012099.3	P4
ERCC1	ENST00000300853.8	c.*197G>T		3_prime_UTR_variant	10/10	1	NM_001983.4	P1

Frequencies

GnomAD3 genomes AF: 0.272 AC: 41313 AN: 151910 Hom.: 5750 Cov.: 31

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

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

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

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	This variant is associated with the following publications: (PMID: 10952103, 18635523, 23203453) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

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

Other links and lift over

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