rs751921616

Variant names:

• chr9-35658026-C-CAGCTTCACAGAGT
• rs751921616
• ENST00000363046.2:n.-8_-7insACTCTGTGAAGCT

Your query was ambiguous. Multiple possible variants found:

• chr9-35658026-C-CAGCTTCACAGAGT
• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGT
• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT
• chr9-35658026-C-CAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGTAGCTTCACAGAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000363046.2(RMRP):​n.-8_-7insACTCTGTGAAGCT variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000277 in 685,526 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: RMRP ENST00000363046.2 upstream_gene
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: -9.77
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 9-35658026-C-CAGCTTCACAGAGT is Pathogenic according to our data. Variant chr9-35658026-C-CAGCTTCACAGAGT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 465205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000363046.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.-8_-7insACTCTGTGAAGCT		upstream_gene	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.-8_-7insACTCTGTGAAGCT		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000483

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: 0.0000634 AC: 8 AN: 126250 AF XY: 0.0000725

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000850

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000841

Gnomad OTH exome AF: 0.000257

GnomAD4 exome AF: 0.0000281 AC: 15 AN: 533404 Hom.: 0 Cov.: 0 AF XY: 0.0000279 AC XY: 8 AN XY: 286710

African (AFR) AF: 0.00 AC: 0 AN: 15384

American (AMR) AF: 0.0000591 AC: 2 AN: 33846

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19606

East Asian (EAS) AF: 0.00 AC: 0 AN: 31716

South Asian (SAS) AF: 0.0000161 AC: 1 AN: 62038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33018

Middle Eastern (MID) AF: 0.000419 AC: 1 AN: 2386

European-Non Finnish (NFE) AF: 0.0000294 AC: 9 AN: 305706

Other (OTH) AF: 0.0000673 AC: 2 AN: 29704

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152122 Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2 AN XY: 74332

African (AFR) AF: 0.0000483 AC: 2 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000158 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Metaphyseal chondrodysplasia, McKusick type (2)
1	-	-	Anauxetic dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-9.8

Splicing

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

Other links and lift over

dbSNP: rs751921616; hg19: chr9-35658023;