7-102478833-A-G

Position:

• chr7-102478833-A-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_006234.6(POLR2J):​c.28T>C​(p.Phe10Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,550 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: POLR2J NM_006234.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.61

Genes affected

POLR2J (HGNC:9197): (RNA polymerase II subunit J) This gene encodes a subunit of RNA polymerase II, the polymerase responsible for synthesizing messenger RNA in eukaryotes. The product of this gene exists as a heterodimer with another polymerase subunit; together they form a core subassembly unit of the polymerase. Two similar genes are located nearby on chromosome 7q22.1 and a pseudogene is found on chromosome 7p13. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR2J	NM_006234.6	c.28T>C	p.Phe10Leu	missense_variant	1/4	ENST00000292614.10	NP_006225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR2J	ENST00000292614.10	c.28T>C	p.Phe10Leu	missense_variant	1/4	1	NM_006234.6	ENSP00000292614.5

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458550 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 725602

Gnomad4 AFR exome AF: 0.00

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: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 29

Bravo AF: 0.00000378

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

Oct 21, 2024

The c.28T>C (p.F10L) alteration is located in exon 1 (coding exon 1) of the POLR2J gene. This alteration results from a T to C substitution at nucleotide position 28, causing the phenylalanine (F) at amino acid position 10 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;.
Eigen	Benign	-0.016
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.0080	N
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.6	M;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.021	D;D
Sift4G	Benign	0.065	T;T
Polyphen		0.036	B;.
Vest4		0.67
MutPred		0.45		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		1.0
MPC		1.6
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.66
gMVP		0.86

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: rs1798503844; hg19: chr7-102119280;