NM_012099.3:c.36C>G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012099.3(POLR1G):c.36C>G(p.Phe12Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00184 in 1,598,288 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00098 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 1 hom. )

Consequence

POLR1G
NM_012099.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.796

Variant links:

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]

POLR1G links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09372342).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1G	NM_012099.3 link	c.36C>G	p.Phe12Leu	missense_variant	Exon 2 of 3	ENST00000309424.8	NP_036231.1	O15446-1
ERCC1	NM_001983.4 link	c.*2568G>C		downstream_gene_variant		ENST00000300853.8	NP_001974.1	P07992-1A0A024R0Q6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8 link	c.36C>G	p.Phe12Leu	missense_variant	Exon 2 of 3	1	NM_012099.3	ENSP00000310966.3		O15446-1
ERCC1	ENST00000300853.8 link	c.*2568G>C		downstream_gene_variant		1	NM_001983.4	ENSP00000300853.3		P07992-1

Frequencies

GnomAD3 genomes

AF:

0.000986

AC:

150

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00179

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00115

AC:

271

AN:

234758

Hom.:

AF XY:

0.00114

AC XY:

146

AN XY:

127636

show subpopulations

Gnomad AFR exome

AF:

0.000502

Gnomad AMR exome

AF:

0.000418

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000287

Gnomad FIN exome

AF:

0.000329

Gnomad NFE exome

AF:

0.00211

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.00193

AC:

2786

AN:

1446002

Hom.:

Cov.:

AF XY:

0.00184

AC XY:

1327

AN XY:

719630

show subpopulations

Gnomad4 AFR exome

AF:

0.000403

Gnomad4 AMR exome

AF:

0.000417

Gnomad4 ASJ exome

AF:

0.0000393

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000287

Gnomad4 FIN exome

AF:

0.000319

Gnomad4 NFE exome

AF:

0.00240

Gnomad4 OTH exome

AF:

0.000937

GnomAD4 genome

AF:

0.000985

AC:

150

AN:

152286

Hom.:

Cov.:

AF XY:

0.000994

AC XY:

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.00179

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00151

Hom.:

Bravo

AF:

0.00102

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.00109

AC:

132

EpiCase

AF:

0.00142

EpiControl

AF:

0.00178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.36C>G (p.F12L) alteration is located in exon 2 (coding exon 2) of the CD3EAP gene. This alteration results from a C to G substitution at nucleotide position 36, causing the phenylalanine (F) at amino acid position 12 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.094

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-4.9

D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0090

D;.

Sift4G

Benign

0.14

T;T

Polyphen

1.0

D;D

Vest4

0.73

MutPred

0.28

Loss of glycosylation at S13 (P = 0.1601);.;

MVP

0.35

MPC

0.69

ClinPred

0.060

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over