19-45407107-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F12S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.796

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]

ACMG classification

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/exons	MANE	UniProt
POLR1G	NM_012099.3	c.36C>G	p.Phe12Leu	missense_variant	2/3	ENST00000309424.8
POLR1G	NM_001297590.3	c.42C>G	p.Phe14Leu	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1G	ENST00000309424.8	c.36C>G	p.Phe12Leu	missense_variant	2/3	1	NM_012099.3	P4
POLR1G	ENST00000589804.1	c.42C>G	p.Phe14Leu	missense_variant	2/3	1		A2
POLR1G	ENST00000592852.1	c.-499C>G		5_prime_UTR_variant	1/2	2
POLR1G	ENST00000590794.1	c.20+389C>G		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.000986 AC: 150 AN: 152168 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00114 AC XY: 146 AN XY: 127636

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.: 1 Cov.: 31 AF XY: 0.00184 AC XY: 1327 AN XY: 719630

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.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74468

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.: 0

Bravo AF: 0.00102

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00186 AC: 16

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

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

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	T
BayesDel_noAF	Benign	-0.10
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.71	T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.62	N;N
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs117289933; hg19: chr19-45910365;