9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT

Position:

• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: intergenic_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -9.77

Genes affected

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT is Pathogenic according to our data. Variant chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT is described in ClinVar as [Pathogenic]. Clinvar id is 1454371.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.35658026_35658027insAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT		intergenic_region
RMRP	NR_003051.4	n.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCTACTCTGTGAAGCTACTCTGTGAAGCT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.-10_-9insACTCTGTGAAGCTACTCTGTGAAGCTACTCTGTGAAGCTACTCTGTGAAGCT		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 0

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 31, 2021

For these reasons, this variant has been classified as Pathogenic. While functional studies for this variant have not been reported, experimental analyses using patient derived cells, as well as in vitro transfection studies, have shown that promoter insertions result in silencing of RMRP transcription and reduced expression of the gene product (PMID: 11207361, 16254002). While this particular variant has not been reported in the literature, it is located in the promoter region between the TATA box and the transcription initiation site, and other insertions and duplications immediately upstream of the coding sequence have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia (CHH-AD) spectrum disorders (PMID: 16244706, 11207361, 12107819). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-35658023;