19-45408417-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012099.3(POLR1G):c.449G>A(p.Cys150Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.988

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32007194).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1G	NM_012099.3	c.449G>A	p.Cys150Tyr	missense_variant	3/3	ENST00000309424.8
ERCC1	NM_001983.4	c.*1258C>T		3_prime_UTR_variant	10/10	ENST00000300853.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1G	ENST00000309424.8	c.449G>A	p.Cys150Tyr	missense_variant	3/3	1	NM_012099.3	P4
ERCC1	ENST00000300853.8	c.*1258C>T		3_prime_UTR_variant	10/10	1	NM_001983.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000202 AC: 5 AN: 247530 Hom.: 0 AF XY: 0.0000149 AC XY: 2 AN XY: 134338

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1461326 Hom.: 0 Cov.: 38 AF XY: 0.00000275 AC XY: 2 AN XY: 726934

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74368

Gnomad4 AFR AF: 0.000193

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.0000793

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2023

The c.449G>A (p.C150Y) alteration is located in exon 3 (coding exon 3) of the CD3EAP gene. This alteration results from a G to A substitution at nucleotide position 449, causing the cysteine (C) at amino acid position 150 to be replaced by a tyrosine (Y). 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.10	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-6.0	D;.
REVEL	Benign	0.20
Sift	Benign	0.044	D;.
Sift4G	Benign	0.092	T;T
Polyphen		0.99	D;D
Vest4		0.36
MutPred		0.48		Gain of phosphorylation at C150 (P = 0.0613);.;
MVP		0.49
MPC		0.84
ClinPred		0.63	D
GERP RS		2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.26
gMVP		0.33

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: rs774936715; hg19: chr19-45911675;