rs875989826

chr6-43521005-AAAG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4_Supporting PP3 PP5_Very_Strong

The NM_203290.4(POLR1C):c.883_885del(p.Lys295del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,068 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: POLR1C NM_203290.4 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.32

Genes affected

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_203290.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 6-43521005-AAAG-A is Pathogenic according to our data. Variant chr6-43521005-AAAG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLR1C	NM_203290.4	c.883_885del	p.Lys295del	inframe_deletion	8/9	ENST00000642195.1
POLR1C	NM_001318876.2	c.883_885del	p.Lys295del	inframe_deletion	8/11
POLR1C	NM_001363658.2	c.883_885del	p.Lys295del	inframe_deletion	8/10
POLR1C	XM_047419577.1	c.883_885del	p.Lys295del	inframe_deletion	8/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLR1C	ENST00000642195.1	c.883_885del	p.Lys295del	inframe_deletion	8/9		NM_203290.4	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152192 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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251486 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1461876 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74356

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypomyelinating leukodystrophy 11 Pathogenic:2 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 07, 2015	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	research	MyeliNeuroGene Lab, McGill University Health Center Research Institute	-	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2016

The c.883_885delAAG likely pathogenic variant in the POLR1C gene has been reported previously in associationwith hypomyelinating leukodystrophy in an individual that also harbored a second variant (Thiffault et al., 2015;Vanderver et al., 2016). The c.883_885delAAG variant causes an in-frame deletion of one amino acid, Lysine 295,denoted p.Lys295del. Lysine is conserved at this position among mammals. The c.883_885delAAG variant was notobserved in approximately 6500 individuals of European and African American ancestry in the NHLBI ExomeSequencing Project, indicating it is not a common benign variant in these populations. Therefore, thec.883_885delAAG variant is a strong candidate for a pathogenic variant, however the possibility it may be a rarebenign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs875989826; hg19: chr6-43488743;