rs1554651513

Positions:

• chr9-35658030-T-TTCACAGAGTAG

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 0.00000942 in 530,596 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:4
• Conservation: PhyloP100: -3.73

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 9-35658030-T-TTCACAGAGTAG is Pathogenic according to our data. Variant chr9-35658030-T-TTCACAGAGTAG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 557339.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.35658030_35658031insTCACAGAGTAG		intergenic_region
RMRP	NR_003051.4	n.-12_-11insCTACTCTGTGA		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RMRP	ENST00000363046.1	n.-14_-13insCTACTCTGTGA		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000241 AC: 3 AN: 124488 Hom.: 0 AF XY: 0.0000147 AC XY: 1 AN XY: 68130

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: 0.0000425

Gnomad OTH exome AF: 0.000262

GnomAD4 exome AF: 0.00000942 AC: 5 AN: 530596 Hom.: 0 Cov.: 0 AF XY: 0.00000702 AC XY: 2 AN XY: 284938

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: 0.00000986

Gnomad4 OTH exome AF: 0.0000677

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Metaphyseal chondrodysplasia, McKusick type Pathogenic:3

Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 01, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 18, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 02, 2024	Variant summary: RMRP n.-23_-13dup11 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). 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. To our knowledge, no occurrence of n.-23_-13dup11 in individuals affected with Cartilage-Hair Hypoplasia and no experimental evidence demonstrating its impact on protein function have been reported. 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). ClinVar contains an entry for this variant (Variation ID: 557339). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Anauxetic dysplasia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 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). This variant occurs in the RMRP gene, which encodes an RNA molecule that does not result in a protein product. This variant is present in population databases (no rsID available, gnomAD 0.005%). 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). ClinVar contains an entry for this variant (Variation ID: 557339). -

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: rs1554651513; hg19: chr9-35658027;