chr2-112547506-A-C

Position:

• chr2-112547506-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_019014.6(POLR1B):​c.431A>C​(p.Lys144Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLR1B NM_019014.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.10

Genes affected

POLR1B (HGNC:20454): (RNA polymerase I subunit B) Eukaryotic RNA polymerase I (pol I) is responsible for the transcription of ribosomal RNA (rRNA) genes and production of rRNA, the primary component of ribosomes. Pol I is a multisubunit enzyme composed of 6 to 14 polypeptides, depending on the species. Most of the mass of the pol I complex derives from the 2 largest subunits, Rpa1 and Rpa2 in yeast. POLR1B is homologous to Rpa2 (Seither and Grummt, 1996 [PubMed 8921381]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), POLR1B. . Gene score misZ 2.9739 (greater than the threshold 3.09). Trascript score misZ 4.7393 (greater than threshold 3.09). GenCC has associacion of gene with Treacher-Collins syndrome, Treacher Collins syndrome 4.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31852105).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1B	NM_019014.6	c.431A>C	p.Lys144Thr	missense_variant	3/15	ENST00000263331.10	NP_061887.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1B	ENST00000263331.10	c.431A>C	p.Lys144Thr	missense_variant	3/15	2	NM_019014.6	ENSP00000263331	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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

Sep 26, 2023

The c.431A>C (p.K144T) alteration is located in exon 3 (coding exon 3) of the POLR1B gene. This alteration results from a A to C substitution at nucleotide position 431, causing the lysine (K) at amino acid position 144 to be replaced by a threonine (T). 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	0.099
BayesDel_addAF	Benign	0.00024	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;.;.;.
Eigen	Benign	0.0079
Eigen_PC	Benign	0.061
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.85	D;D;D;D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	2.0	M;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.051	T;T;T;T
Sift4G	Benign	0.44	T;T;T;T
Polyphen		0.66	P;.;.;B
Vest4		0.29
MutPred		0.71		.;Gain of ubiquitination at K180 (P = 0.0606);.;.;
MVP		0.52
MPC		0.26
ClinPred		0.75	D
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1396054466; hg19: chr2-113305083;