9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT

Position:

• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT

Variant summary

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

The variant allele was found at a frequency of 0.00000562 in 533,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: intergenic_region
• Clinical Significance: Likely 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-CAGCTTCACAGAGTAGCTTCACAGAGT is Pathogenic according to our data. Variant chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067465.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_35658027insAGCTTCACAGAGTAGCTTCACAGAGT		intergenic_region
RMRP	NR_003051.4	n.-8_-7insACTCTGTGAAGCTACTCTGTGAAGCT		upstream_gene_variant

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000792 AC: 1 AN: 126250 Hom.: 0 AF XY: 0.0000145 AC XY: 1 AN XY: 68980

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000425

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000562 AC: 3 AN: 533404 Hom.: 0 Cov.: 0 AF XY: 0.00000698 AC XY: 2 AN XY: 286710

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000295

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000654

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Anauxetic dysplasia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

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). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is present in population databases (no rsID available, gnomAD 0.004%). 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

LitVar

Other links and lift over

dbSNP: rs751921616; hg19: chr9-35658023;