rs1554651524

Positions:

• chr9-35658031-T-TCACAGAGTAG

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 0.00000189 in 530,404 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: 0.0000019 (0 hom.)
• Consequence: intergenic_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -3.94

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 9-35658031-T-TCACAGAGTAG is Pathogenic according to our data. Variant chr9-35658031-T-TCACAGAGTAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557391.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.35658031_35658032insCACAGAGTAG		intergenic_region
RMRP	NR_003051.4	n.-13_-12insCTACTCTGTG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.-15_-14insCTACTCTGTG		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000189 AC: 1 AN: 530404 Hom.: 0 Cov.: 0 AF XY: 0.00000351 AC XY: 1 AN XY: 284796

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: 0.00000329

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 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2024	Variant summary: RMRP n.-23_-14dup10 is located in the promoter region of the RMRP gene which is located between the TATA box (at position -33 to -25) and the transcription initiation site (at +1). This variant is also known as -15_-24dupCTACTCTGTG. Other insertions or duplications in the promoter region of RMRP have been classified as pathogenic (internally and in ClinVar). The variant was absent in 127922 control chromosomes. n.-23_-14dup10 has been reported in the literature in the compound heterozygous state together with a pathogenic variant in an individual affected with Cartilage-Hair Hypoplasia (e.g.,Hermanns_2006, Hermanns_2005). At least one publication reports experimental evidence evaluating an impact on protein function and found that the variant results in reduced promoter activity compared to the WT RMRP promoter in vitro (Hermanns_2005). Additionally, many other insertions or duplications in the promoter region of RMRP have been reported in affected individuals in the literature (e.g. PMIDs: 21956908, 21396580) and have been demonstrated through functional studies to lead to reduced RMRP transcription (e.g. PMIDs: 11207361, 16254002).The following publications have been ascertained in the context of this evaluation (PMID: 16838329, 16254002). ClinVar contains an entry for this variant (Variation ID: 557391). Based on the evidence outlined above, the variant was classified as pathogenic. -

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 25, 2021

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. This variant has been observed in individual(s) with cartilage-hair hypoplasia (PMID: 16254002, 16838329). This variant is also known as -15_-24dupCTACTCTGTG. 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). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant alters RMRP gene expression (PMID: 16254002). -

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: rs1554651524; hg19: chr9-35658028;