rs735482

Variant names:

• chr19-45408744-A-C
• rs735482
• NM_012099.3:c.776A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-45408744-A-C
• chr19-45408744-A-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.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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 0.0620
• Publications: 102 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 (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 VariationId 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 rank	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.776A>C	p.Lys259Thr	missense_variant	Exon 3 of 3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.*931T>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.776A>C	p.Lys259Thr	missense_variant	Exon 3 of 3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8	c.*931T>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001983.4	ENSP00000300853.3

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

GnomAD2 exomes AF: 0.208 AC: 51762 AN: 248372 AF XY: 0.204

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 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

African (AFR) AF: 0.287 AC: 9599 AN: 33478

American (AMR) AF: 0.265 AC: 11836 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 3663 AN: 26136

East Asian (EAS) AF: 0.461 AC: 18318 AN: 39700

South Asian (SAS) AF: 0.263 AC: 22709 AN: 86256

European-Finnish (FIN) AF: 0.158 AC: 8447 AN: 53352

Middle Eastern (MID) AF: 0.158 AC: 913 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154176 AN: 1111996

Other (OTH) AF: 0.176 AC: 10605 AN: 60394

GnomAD4 genome AF: 0.201 AC: 30519 AN: 151836 Hom.: 3539 Cov.: 31 AF XY: 0.204 AC XY: 15178 AN XY: 74224

African (AFR) AF: 0.282 AC: 11687 AN: 41382

American (AMR) AF: 0.210 AC: 3199 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 475 AN: 3468

East Asian (EAS) AF: 0.443 AC: 2276 AN: 5142

South Asian (SAS) AF: 0.271 AC: 1298 AN: 4786

European-Finnish (FIN) AF: 0.144 AC: 1527 AN: 10572

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9470 AN: 67944

Other (OTH) AF: 0.198 AC: 416 AN: 2104

Alfa AF: 0.160 Hom.: 4678

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;.
PhyloP100		0.062
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
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: rs735482; hg19: chr19-45912002; COSMIC: COSV50004018; COSMIC: COSV50004018;