NM_012099.3:c.1180G>A

Variant names:

• chr19-45409148-G-A
• rs2336219
• NM_012099.3:c.1180G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_012099.3(POLR1G):​c.1180G>A​(p.Asp394Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,613,748 control chromosomes in the GnomAD database, including 26,540 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (3453 hom., cov: 31)
  • Exomes 𝑓: 0.16 (23087 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.874
• Publications: 66 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2935867E-4).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.1180G>A	p.Asp394Asn	missense_variant	Exon 3 of 3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.*527C>T		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.1180G>A	p.Asp394Asn	missense_variant	Exon 3 of 3	1	NM_012099.3	ENSP00000310966.3
ERCC1	ENST00000300853.8	c.*527C>T		3_prime_UTR_variant	Exon 10 of 10	1	NM_001983.4	ENSP00000300853.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30159 AN: 151802 Hom.: 3449 Cov.: 31

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.209

Gnomad ASJ AF: 0.137

Gnomad EAS AF: 0.444

Gnomad SAS AF: 0.273

Gnomad FIN AF: 0.145

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.208 AC: 51402 AN: 247428 AF XY: 0.203

Gnomad AFR exome AF: 0.281

Gnomad AMR exome AF: 0.273

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.141

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.164 AC: 239888 AN: 1461830 Hom.: 23087 Cov.: 46 AF XY: 0.167 AC XY: 121149 AN XY: 727218

African (AFR) AF: 0.278 AC: 9307 AN: 33480

American (AMR) AF: 0.264 AC: 11817 AN: 44716

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

East Asian (EAS) AF: 0.461 AC: 18307 AN: 39700

South Asian (SAS) AF: 0.263 AC: 22724 AN: 86258

European-Finnish (FIN) AF: 0.158 AC: 8458 AN: 53392

Middle Eastern (MID) AF: 0.158 AC: 909 AN: 5768

European-Non Finnish (NFE) AF: 0.139 AC: 154121 AN: 1111984

Other (OTH) AF: 0.175 AC: 10582 AN: 60396

GnomAD4 genome AF: 0.199 AC: 30190 AN: 151918 Hom.: 3453 Cov.: 31 AF XY: 0.202 AC XY: 15025 AN XY: 74262

African (AFR) AF: 0.274 AC: 11339 AN: 41398

American (AMR) AF: 0.209 AC: 3191 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.137 AC: 474 AN: 3458

East Asian (EAS) AF: 0.443 AC: 2281 AN: 5146

South Asian (SAS) AF: 0.272 AC: 1308 AN: 4802

European-Finnish (FIN) AF: 0.145 AC: 1539 AN: 10594

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

European-Non Finnish (NFE) AF: 0.139 AC: 9471 AN: 67950

Other (OTH) AF: 0.197 AC: 415 AN: 2110

Alfa AF: 0.162 Hom.: 11373

Bravo AF: 0.205

TwinsUK AF: 0.143 AC: 532

ALSPAC AF: 0.146 AC: 564

ESP6500AA AF: 0.253 AC: 1113

ESP6500EA AF: 0.132 AC: 1133

ExAC AF: 0.206 AC: 25015

Asia WGS AF: 0.338 AC: 1173 AN: 3478

EpiCase AF: 0.142

EpiControl AF: 0.139

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.86	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.071
DANN	Benign	0.49
DEOGEN2	Benign	0.0049	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0077	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.00023	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.5	N;.
PhyloP100		-0.87
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.2	N;.
REVEL	Benign	0.032
Sift	Benign	1.0	T;.
Sift4G	Benign	0.83	T;T
Polyphen		0.0	B;B
Vest4		0.016
MPC		0.14
ClinPred		0.0017	T
GERP RS		-2.1
Varity_R		0.032
gMVP		0.012
Mutation Taster		=98/2	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: rs2336219; hg19: chr19-45912406; COSMIC: COSV50004019; COSMIC: COSV50004019;