19-45408744-A-C

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0620

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=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	UniProt
POLR1G	NM_012099.3	c.776A>C	p.Lys259Thr	missense_variant	3/3	ENST00000309424.8
ERCC1	NM_001983.4	c.*931T>G		3_prime_UTR_variant	10/10	ENST00000300853.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1G	ENST00000309424.8	c.776A>C	p.Lys259Thr	missense_variant	3/3	1	NM_012099.3	P4
ERCC1	ENST00000300853.8	c.*931T>G		3_prime_UTR_variant	10/10	1	NM_001983.4	P1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30488 AN: 151718 Hom.: 3535 Cov.: 31

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

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.: 43 AF XY: 0.167 AC XY: 121295 AN XY: 727184

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.: 31 AF XY: 0.204 AC XY: 15178 AN XY: 74224

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	11
Dann	Benign	0.76
DEOGEN2	Benign	0.0095	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0057	N
LIST_S2	Benign	0.14	T;T
MetaRNN	Benign	0.00076	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.90	N;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.26	T
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	T
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

Other links and lift over

dbSNP: rs735482; hg19: chr19-45912002; COSMIC: COSV50004018; COSMIC: COSV50004018;