rs3212989

Variant names:

• chr19-45408812-A-G
• rs3212989
• NM_012099.3:c.844A>G

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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
• Publications: 12 publications found

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]

ERCC1 Gene-Disease associations (from GenCC):

• cerebrooculofacioskeletal syndrome 4

  Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 235480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0654 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012099.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1G	NM_012099.3	MANE Select	c.844A>G	p.Thr282Ala	missense	Exon 3 of 3	NP_036231.1	O15446-1
	ERCC1	NM_001983.4	MANE Select	c.*863T>C		3_prime_UTR	Exon 10 of 10	NP_001974.1	P07992-1
	POLR1G	NM_001297590.3		c.850A>G	p.Thr284Ala	missense	Exon 3 of 3	NP_001284519.1	O15446-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1G	ENST00000309424.8	TSL:1 MANE Select	c.844A>G	p.Thr282Ala	missense	Exon 3 of 3	ENSP00000310966.3	O15446-1
	POLR1G	ENST00000589804.1	TSL:1	c.850A>G	p.Thr284Ala	missense	Exon 3 of 3	ENSP00000465099.1	O15446-2
	ERCC1	ENST00000300853.8	TSL:1 MANE Select	c.*863T>C		3_prime_UTR	Exon 10 of 10	ENSP00000300853.3	P07992-1

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

GnomAD2 exomes AF: 0.00558 AC: 1387 AN: 248640 AF XY: 0.00437

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 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

African (AFR) AF: 0.0729 AC: 2441 AN: 33478

American (AMR) AF: 0.00402 AC: 180 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00991 AC: 259 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000185 AC: 16 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53358

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5768

European-Non Finnish (NFE) AF: 0.000245 AC: 272 AN: 1112008

Other (OTH) AF: 0.00530 AC: 320 AN: 60392

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

African (AFR) AF: 0.0675 AC: 2800 AN: 41498

American (AMR) AF: 0.00667 AC: 102 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 33 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68006

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00860 Hom.: 39

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	2	not provided (3)
-	-	1	Cerebrooculofacioskeletal syndrome 4 (1)
-	-	1	ERCC1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.14	N
PhyloP100		-2.0
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.031
Sift	Benign	0.27	T
Sift4G	Benign	0.78	T
Polyphen		0.011	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
Mutation Taster		=98/2	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs3212989; hg19: chr19-45912070;