2-86040482-TG-T

Position:

• chr2-86040482-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_015425.6(POLR1A):​c.3649delC​(p.Gln1217fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR1A NM_015425.6 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60

Genes affected

POLR1A (HGNC:17264): (RNA polymerase I subunit A) The protein encoded by this gene is the largest subunit of the RNA polymerase I complex. The encoded protein represents the catalytic subunit of the complex, which transcribes DNA into ribosomal RNA precursors. Defects in this gene are a cause of the Cincinnati type of acrofacial dysostosis. [provided by RefSeq, May 2016]

POLR1A (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-86040482-TG-T is Pathogenic according to our data. Variant chr2-86040482-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 203464.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-86040482-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1A	NM_015425.6	c.3649delC	p.Gln1217fs	frameshift_variant	25/34	ENST00000263857.11	NP_056240.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1A	ENST00000263857.11	c.3649delC	p.Gln1217fs	frameshift_variant	25/34	1	NM_015425.6	ENSP00000263857.6
POLR1A	ENST00000409681.1	c.3649delC	p.Gln1217fs	frameshift_variant	25/34	5		ENSP00000386300.1
POLR1A	ENST00000462078.1	n.37delC		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Acrofacial dysostosis Cincinnati type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 07, 2015

- -

Computational scores

Source: dbNSFP v4.3

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: rs875989814; hg19: chr2-86267605;