chr19-45406703-G-A

Variant names:

• chr19-45406703-G-A
• rs1018663455
• NM_012099.3:c.7G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012099.3(POLR1G):​c.7G>A​(p.Glu3Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,538,912 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: POLR1G NM_012099.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.22

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07580426).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLR1G	NM_012099.3	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 3	ENST00000309424.8	NP_036231.1
POLR1G	NM_001297590.3	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 3		NP_001284519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLR1G	ENST00000309424.8	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 3	1	NM_012099.3	ENSP00000310966.3
POLR1G	ENST00000589804.1	c.7G>A	p.Glu3Lys	missense_variant	Exon 1 of 3	1		ENSP00000465099.1
POLR1G	ENST00000590794.1	c.4G>A	p.Glu2Lys	missense_variant	Exon 1 of 2	5		ENSP00000466503.1
POLR1G	ENST00000592852	c.-903G>A		5_prime_UTR_variant	Exon 1 of 2	2		ENSP00000467771.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 142414 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000159 AC: 22 AN: 1386758 Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 10 AN XY: 684352

African (AFR) AF: 0.00 AC: 0 AN: 30468

American (AMR) AF: 0.00 AC: 0 AN: 31892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24744

East Asian (EAS) AF: 0.00 AC: 0 AN: 34266

South Asian (SAS) AF: 0.00 AC: 0 AN: 77706

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 0.0000158 AC: 17 AN: 1075408

Other (OTH) AF: 0.0000869 AC: 5 AN: 57510

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74334

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>A (p.E3K) alteration is located in exon 1 (coding exon 1) of the CD3EAP gene. This alteration results from a G to A substitution at nucleotide position 7, causing the glutamic acid (E) at amino acid position 3 to be replaced by a lysine (K). 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	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0079	T;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.56	T;T
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.076	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-0.83	N;.
REVEL	Benign	0.10
Sift	Benign	0.24	T;.
Sift4G	Benign	0.16	T;T
Polyphen		0.072	B;B
Vest4		0.12
MutPred		0.12		Gain of ubiquitination at E3 (P = 0.0039);Gain of ubiquitination at E3 (P = 0.0039);
MVP		0.35
MPC		0.17
ClinPred		0.39	T
GERP RS		4.0
PromoterAI		-0.081
Varity_R		0.25
gMVP		0.54
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1018663455; hg19: chr19-45909961;