rs3212985

Variant names:

• chr19-45409828-C-G
• rs3212985
• NM_012099.3:c.*327C>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.*327C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.187 in 706,458 control chromosomes in the GnomAD database, including 14,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2446 hom., cov: 30)
  • Exomes 𝑓: 0.19 (11646 hom.)
• Consequence: POLR1G NM_012099.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184
• Publications: 7 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• 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 (BayesDel_noAF=-0.92).
• BP6: Variant 19-45409828-C-G is Benign according to our data. Variant chr19-45409828-C-G is described in ClinVar as Benign. ClinVar VariationId is 1236680.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.*327C>G		3_prime_UTR_variant	Exon 3 of 3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.844-103G>C		intron_variant	Intron 9 of 9	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.*327C>G		3_prime_UTR_variant	Exon 3 of 3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8	c.844-103G>C		intron_variant	Intron 9 of 9	1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24750 AN: 151098 Hom.: 2449 Cov.: 30

Gnomad AFR AF: 0.0809

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.169

Gnomad NFE AF: 0.221

Gnomad OTH AF: 0.175

GnomAD4 exome AF: 0.193 AC: 107326 AN: 555256 Hom.: 11646 Cov.: 0 AF XY: 0.197 AC XY: 59162 AN XY: 299624

African (AFR) AF: 0.0818 AC: 1260 AN: 15406

American (AMR) AF: 0.114 AC: 3833 AN: 33750

Ashkenazi Jewish (ASJ) AF: 0.220 AC: 4333 AN: 19690

East Asian (EAS) AF: 0.0106 AC: 340 AN: 31934

South Asian (SAS) AF: 0.226 AC: 13957 AN: 61766

European-Finnish (FIN) AF: 0.174 AC: 8330 AN: 47882

Middle Eastern (MID) AF: 0.251 AC: 607 AN: 2418

European-Non Finnish (NFE) AF: 0.221 AC: 68911 AN: 312338

Other (OTH) AF: 0.191 AC: 5755 AN: 30072

GnomAD4 genome AF: 0.164 AC: 24743 AN: 151202 Hom.: 2446 Cov.: 30 AF XY: 0.162 AC XY: 11956 AN XY: 73836

African (AFR) AF: 0.0809 AC: 3338 AN: 41286

American (AMR) AF: 0.138 AC: 2098 AN: 15158

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 768 AN: 3464

East Asian (EAS) AF: 0.0122 AC: 63 AN: 5184

South Asian (SAS) AF: 0.212 AC: 1014 AN: 4778

European-Finnish (FIN) AF: 0.174 AC: 1793 AN: 10294

Middle Eastern (MID) AF: 0.168 AC: 49 AN: 292

European-Non Finnish (NFE) AF: 0.221 AC: 14946 AN: 67740

Other (OTH) AF: 0.173 AC: 362 AN: 2096

Alfa AF: 0.189 Hom.: 356

Bravo AF: 0.156

Asia WGS AF: 0.0920 AC: 324 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 11, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.39
DANN	Benign	0.58
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs3212985; hg19: chr19-45913086;