chr19-45407106-T-C

Variant names:

• chr19-45407106-T-C
• NM_012099.3:c.35T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012099.3(POLR1G):​c.35T>C​(p.Phe12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,445,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F12L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 0 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Cockayne syndrome type 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• COFS syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.777

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012099.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1G	NM_012099.3	MANE Select	c.35T>C	p.Phe12Ser	missense	Exon 2 of 3	NP_036231.1	O15446-1
	POLR1G	NM_001297590.3		c.41T>C	p.Phe14Ser	missense	Exon 2 of 3	NP_001284519.1	O15446-2
	ERCC1	NM_001983.4	MANE Select	c.*2569A>G		downstream_gene	N/A	NP_001974.1	P07992-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLR1G	ENST00000309424.8	TSL:1 MANE Select	c.35T>C	p.Phe12Ser	missense	Exon 2 of 3	ENSP00000310966.3	O15446-1
	POLR1G	ENST00000589804.1	TSL:1	c.41T>C	p.Phe14Ser	missense	Exon 2 of 3	ENSP00000465099.1	O15446-2
	POLR1G	ENST00000592852.1	TSL:2	c.-500T>C		5_prime_UTR	Exon 1 of 2	ENSP00000467771.1	K7EQC8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445204 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 719186

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000310 AC: 1 AN: 32220

American (AMR) AF: 0.00 AC: 0 AN: 38106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25422

East Asian (EAS) AF: 0.00 AC: 0 AN: 39502

South Asian (SAS) AF: 0.00 AC: 0 AN: 83588

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53306

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107624

Other (OTH) AF: 0.00 AC: 0 AN: 59720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.1	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.073	T
Polyphen		1.0	D
Vest4		0.83
MutPred		0.21		Gain of phosphorylation at F12 (P = 0.0215)
MVP		0.44
MPC		0.86
ClinPred		0.99	D
GERP RS		3.8
PromoterAI		-0.0028	Neutral
Varity_R		0.56
gMVP		0.82
Mutation Taster		=85/15	polymorphism

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

hg19: chr19-45910364;