rs3212989

Positions:

• chr19-45408812-A-G

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.844A>G​(p.Thr282Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,614,016 control chromosomes in the GnomAD database, including 167 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (76 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (91 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:5
• Conservation: PhyloP100: -2.04

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=0.0020589828).
• BP6: Variant 19-45408812-A-G is Benign according to our data. Variant chr19-45408812-A-G is described in ClinVar as [Benign]. Clinvar id is 235480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-45408812-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.844A>G	p.Thr282Ala	missense_variant	3/3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.*863T>C		3_prime_UTR_variant	10/10	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.844A>G	p.Thr282Ala	missense_variant	3/3	1	NM_012099.3	ENSP00000310966	P4
ERCC1	ENST00000300853.8	c.*863T>C		3_prime_UTR_variant	10/10	1	NM_001983.4	ENSP00000300853	P1

Frequencies

GnomAD3 genomes AF: 0.0196 AC: 2988 AN: 152076 Hom.: 76 Cov.: 31

Gnomad AFR AF: 0.0676

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00668

Gnomad ASJ AF: 0.00953

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.0124

GnomAD3 exomes AF: 0.00558 AC: 1387 AN: 248640 Hom.: 39 AF XY: 0.00437 AC XY: 589 AN XY: 134650

Gnomad AFR exome AF: 0.0672

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0112

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000387

Gnomad OTH exome AF: 0.00278

GnomAD4 exome AF: 0.00241 AC: 3521 AN: 1461822 Hom.: 91 Cov.: 43 AF XY: 0.00216 AC XY: 1574 AN XY: 727198

Gnomad4 AFR exome AF: 0.0729

Gnomad4 AMR exome AF: 0.00402

Gnomad4 ASJ exome AF: 0.00991

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000245

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.0196 AC: 2989 AN: 152194 Hom.: 76 Cov.: 31 AF XY: 0.0192 AC XY: 1430 AN XY: 74418

Gnomad4 AFR AF: 0.0675

Gnomad4 AMR AF: 0.00667

Gnomad4 ASJ AF: 0.00953

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.00889 Hom.: 28

Bravo AF: 0.0222

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0672 AC: 296

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00661 AC: 803

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 15, 2019	- -
Pathogenic, flagged submission	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 28, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.082, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Cerebrooculofacioskeletal syndrome 4 Benign:1

Benign, no assertion criteria provided

curation

Reproductive Health Research and Development, BGI Genomics

Jan 06, 2020

NM_001297590.1:c.850A>G in ghe gene CD3EAP has an allele frequency of 0.067 in African subpopulation in the gnomAD database. A total of 52 homozygous occurrences are observed in the gnomAD database. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2. -

ERCC1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 20, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.10
DANN	Benign	0.65
DEOGEN2	Benign	0.018	T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0021	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N;.
REVEL	Benign	0.031
Sift	Benign	0.27	T;.
Sift4G	Benign	0.78	T;T
Polyphen		0.011	B;B
Vest4		0.021
MVP		0.067
MPC		0.17
ClinPred		0.0068	T
GERP RS		-6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.053

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: rs3212989; hg19: chr19-45912070;