rs1554651499

Variant names:

• chr9-35658029-C-CTTCACAGAGTAGTA
• rs1554651499
• ENST00000363046.2:n.-11_-10insTACTACTCTGTGAA

Your query was ambiguous. Multiple possible variants found:

• chr9-35658029-C-CTTCACAGAGTAGTA
• chr9-35658029-C-CTTCACAGAGTAGTATTCACAGAGTAGTA

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 PP5_Very_Strong

The NR_003051.4(RMRP):​n.-11_-10insTACTACTCTGTGAA variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000233 in 685,280 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001414047: 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).". The gene RMRP is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -4.18
• Publications: 0 publications found

Genes affected

RMRP (HGNC:10031): (RNA component of mitochondrial RNA processing endoribonuclease) This gene encodes the RNA component of mitochondrial RNA processing endoribonuclease, which cleaves mitochondrial RNA at a priming site of mitochondrial DNA replication. This RNA also interacts with the telomerase reverse transcriptase catalytic subunit to form a distinct ribonucleoprotein complex that has RNA-dependent RNA polymerase activity and produces double-stranded RNAs that can be processed into small interfering RNA. Mutations in this gene are associated with cartilage-hair hypoplasia.[provided by RefSeq, Mar 2010]

RMRP Gene-Disease associations (from GenCC):

• cartilage-hair hypoplasia

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Myriad Women's Health

ACMG classification

Specifications for RMRP are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001414047: 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).
• PP5: Variant 9-35658029-C-CTTCACAGAGTAGTA is Pathogenic according to our data. Variant chr9-35658029-C-CTTCACAGAGTAGTA is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 551137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_003051.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.-11_-10insTACTACTCTGTGAA		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.-11_-10insTACTACTCTGTGAA		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000794 AC: 1 AN: 125872 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000211

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000263 AC: 14 AN: 533082 Hom.: 0 Cov.: 0 AF XY: 0.0000279 AC XY: 8 AN XY: 286548

African (AFR) AF: 0.00 AC: 0 AN: 15374

American (AMR) AF: 0.00 AC: 0 AN: 33814

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19508

East Asian (EAS) AF: 0.00 AC: 0 AN: 31712

South Asian (SAS) AF: 0.00 AC: 0 AN: 61988

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2388

European-Non Finnish (NFE) AF: 0.0000425 AC: 13 AN: 305612

Other (OTH) AF: 0.0000337 AC: 1 AN: 29676

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152198 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	Anauxetic dysplasia (1)
1	-	-	Metaphyseal chondrodysplasia, McKusick type (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-4.2

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1554651499;

hg19: chr9-35658026;