19-45407106-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 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	UniProt
POLR1G	NM_012099.3	c.35T>C	p.Phe12Ser	missense_variant	2/3	ENST00000309424.8
POLR1G	NM_001297590.3	c.41T>C	p.Phe14Ser	missense_variant	2/3

Ensembl

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

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

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.: 32

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

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	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;T
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.8	L;.
MutationTaster	Benign	0.64	D;D
PrimateAI	Uncertain	0.71	T
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	D
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.

Other links and lift over

hg19: chr19-45910364;