rs2336219

Positions:

• chr19-45409148-G-A
• chr19-45409148-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.1180G>A	p.Asp394Asn	missense_variant	3/3	ENST00000309424.8	NP_036231.1
ERCC1	NM_001983.4	c.*527C>T		3_prime_UTR_variant	10/10	ENST00000300853.8	NP_001974.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.1180G>A	p.Asp394Asn	missense_variant	3/3	1	NM_012099.3	ENSP00000310966	P4
ERCC1	ENST00000300853.8	c.*527C>T		3_prime_UTR_variant	10/10	1	NM_001983.4	ENSP00000300853	P1

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

GnomAD3 exomes AF: 0.208 AC: 51402 AN: 247428 Hom.: 6404 AF XY: 0.203 AC XY: 27387 AN XY: 134592

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 SAS exome AF: 0.264

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

Gnomad4 AFR exome AF: 0.278

Gnomad4 AMR exome AF: 0.264

Gnomad4 ASJ exome AF: 0.140

Gnomad4 EAS exome AF: 0.461

Gnomad4 SAS exome AF: 0.263

Gnomad4 FIN exome AF: 0.158

Gnomad4 NFE exome AF: 0.139

Gnomad4 OTH exome AF: 0.175

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

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.209

Gnomad4 ASJ AF: 0.137

Gnomad4 EAS AF: 0.443

Gnomad4 SAS AF: 0.272

Gnomad4 FIN AF: 0.145

Gnomad4 NFE AF: 0.139

Gnomad4 OTH AF: 0.197

Alfa AF: 0.158 Hom.: 5719

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;.
MutationTaster	Benign	1.0	P;P;P;P
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

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: rs2336219; hg19: chr19-45912406; COSMIC: COSV50004019; COSMIC: COSV50004019;