13-27622945-GCTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGA-G

Position:

• chr13-27622945-GCTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGA-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_015972.4(POLR1D):​c.99_144delTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGAC​(p.Gly34fs) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLR1D NM_015972.4 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.62

Genes affected

POLR1D (HGNC:20422): (RNA polymerase I and III subunit D) The protein encoded by this gene is a component of the RNA polymerase I and RNA polymerase III complexes, which function in the synthesis of ribosomal RNA precursors and small RNAs, respectively. Mutations in this gene are a cause of Treacher Collins syndrome (TCS), a craniofacial development disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 18 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-27622945-GCTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGA-G is Pathogenic according to our data. Variant chr13-27622945-GCTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 451304.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLR1D	NM_015972.4	c.99_144delTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGAC	p.Gly34fs	frameshift_variant	2/2	ENST00000302979.5	NP_057056.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLR1D	ENST00000302979.5	c.99_144delTGGAACAGATAGACACTGTGTGACATTTGTATTGCACGAGGAAGAC	p.Gly34fs	frameshift_variant	2/2	1	NM_015972.4	ENSP00000302478.4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2023

Frameshift variant predicted to result in abnormal protein length as the last 100 amino acids are replaced with 2 different amino acids, and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555271298; hg19: chr13-28197082;