rs1554651532

Positions:

• chr9-35658032-C-CACAGAGTAGT

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The variant allele was found at a frequency of 0.00000944 in 529,916 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: 0.0000094 (0 hom.)
• Consequence: intergenic_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -3.42

Genes affected

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-35658032-C-CACAGAGTAGT is Pathogenic according to our data. Variant chr9-35658032-C-CACAGAGTAGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 550938.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.35658032_35658033insACAGAGTAGT		intergenic_region
RMRP	NR_003051.4	n.-14_-13insACTACTCTGT		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.-16_-15insACTACTCTGT		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000944 AC: 5 AN: 529916 Hom.: 0 Cov.: 0 AF XY: 0.00000351 AC XY: 1 AN XY: 284514

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000165

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 22, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Biologia Molecular/Medicina Genomica - IFF/Fiocruz, Instituto Fernandes Figueira, Fundacao Oswaldo Cruz	Jan 25, 2024	The variant n.-23_-14dupACTACTCTGT was identified in a compound heterozygous state with another variant in the transcribed region of RMRP gene in an individual affected with Cartilage-Hair Hypoplasia. This alteration is located within the promoter region of the RMRP gene, which encodes an untranslated RNA. Segregation analysis showed that each of the unaffected parents was heterozygous for one of the two variants. Other insertions and duplications in this region have been reported in individuals affected with cartilage-hair hypoplasia-anauxetic dysplasia spectrum disorders (PMID: 11207361, 21956908, 21396580). This variant involves the duplication of 10 nucleotides between the TATA box and the transcription initiation site and functional studies have shown that this type of alteration result in reduced expression of the RMRP gene (PMIDs: 11207361, 16254002). For these reasons, this variant has been classified as Pathogenic. -

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 09, 2023

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). This variant is not present in population databases (gnomAD no frequency). 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: rs1554651532; hg19: chr9-35658029;