Variant chr19-45407106-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000309424.8(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
ENST00000309424.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.90

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.777

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1G	NM_012099.3 linkuse as main transcript	c.35T>C	p.Phe12Ser	missense_variant	2/3	ENST00000309424.8	NP_036231.1
POLR1G	NM_001297590.3 linkuse as main transcript	c.41T>C	p.Phe14Ser	missense_variant	2/3		NP_001284519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8 linkuse as main transcript	c.35T>C	p.Phe12Ser	missense_variant	2/3	1	NM_012099.3	ENSP00000310966	P4	O15446-1
POLR1G	ENST00000589804.1 linkuse as main transcript	c.41T>C	p.Phe14Ser	missense_variant	2/3	1		ENSP00000465099	A2	O15446-2
POLR1G	ENST00000592852.1 linkuse as main transcript	c.-500T>C		5_prime_UTR_variant	1/2	2		ENSP00000467771
POLR1G	ENST00000590794.1 linkuse as main transcript	c.20+388T>C		intron_variant		5		ENSP00000466503

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445204

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719186

show subpopulations

Gnomad4 AFR exome

AF:

0.0000310

Gnomad4 AMR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2022

The c.35T>C (p.F12S) alteration is located in exon 2 (coding exon 2) of the CD3EAP gene. This alteration results from a T to C substitution at nucleotide position 35, causing the phenylalanine (F) at amino acid position 12 to be replaced by a serine (S). 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

0.93

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.030

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.8

L;.

MutationTaster

Benign

0.64

D;D

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.1

D;.

REVEL

Benign

0.27

Sift

Uncertain

0.0010

D;.

Sift4G

Benign

0.073

T;T

Polyphen

1.0

D;D

Vest4

0.83

MutPred

0.21

Gain of phosphorylation at F12 (P = 0.0215);.;

MVP

0.44

MPC

0.86

ClinPred

0.99

GERP RS

3.8

Varity_R

0.56

gMVP

0.82

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over