19-45409835-T-C

Position:

• chr19-45409835-T-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.*334T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 697,704 control chromosomes in the GnomAD database, including 78,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (19099 hom., cov: 29)
  • Exomes 𝑓: 0.45 (59347 hom.)
• Consequence: POLR1G NM_012099.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.198

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 19-45409835-T-C is Benign according to our data. Variant chr19-45409835-T-C is described in ClinVar as [Benign]. Clinvar id is 1275555.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.732 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.*334T>C		3_prime_UTR_variant	3/3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.844-110A>G		intron_variant		ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.*334T>C		3_prime_UTR_variant	3/3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8	c.844-110A>G		intron_variant		1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73232 AN: 150610 Hom.: 19075 Cov.: 29

Gnomad AFR AF: 0.624

Gnomad AMI AF: 0.476

Gnomad AMR AF: 0.567

Gnomad ASJ AF: 0.385

Gnomad EAS AF: 0.752

Gnomad SAS AF: 0.578

Gnomad FIN AF: 0.361

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.473

GnomAD4 exome AF: 0.449 AC: 245715 AN: 546986 Hom.: 59347 Cov.: 0 AF XY: 0.453 AC XY: 133607 AN XY: 295052

Gnomad4 AFR exome AF: 0.614

Gnomad4 AMR exome AF: 0.663

Gnomad4 ASJ exome AF: 0.386

Gnomad4 EAS exome AF: 0.722

Gnomad4 SAS exome AF: 0.568

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.450

GnomAD4 genome AF: 0.486 AC: 73302 AN: 150718 Hom.: 19099 Cov.: 29 AF XY: 0.489 AC XY: 35980 AN XY: 73520

Gnomad4 AFR AF: 0.624

Gnomad4 AMR AF: 0.567

Gnomad4 ASJ AF: 0.385

Gnomad4 EAS AF: 0.752

Gnomad4 SAS AF: 0.576

Gnomad4 FIN AF: 0.361

Gnomad4 NFE AF: 0.383

Gnomad4 OTH AF: 0.476

Alfa AF: 0.391 Hom.: 1960

Bravo AF: 0.508

Asia WGS AF: 0.659 AC: 2293 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 11, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.84

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: rs1007616; hg19: chr19-45913093;