9-35657948-T-C

Variant names:

• chr9-35657948-T-C
• rs199476103
• ENST00000363046.2:n.72A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 8P and 2B. PP5_Very_Strong BP4 BS2_Supporting

The NR_003051.4(RMRP):​n.72A>G variant causes a non coding transcript exon change. The variant allele was found at a frequency of 0.00117 in 700,414 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: RMRP NR_003051.4 non_coding_transcript_exon
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:20
• Conservation: PhyloP100: 7.16
• Publications: 12 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: G2P, ClinGen, Myriad Women’s Health, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PP5: Variant 9-35657948-T-C is Pathogenic according to our data. Variant chr9-35657948-T-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 14208.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.15). . Strength limited to SUPPORTING due to the PP5.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.72A>G		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.72A>G		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00150 AC: 228 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000874 AC: 114 AN: 130486 AF XY: 0.000842

Gnomad AFR exome AF: 0.000164

Gnomad AMR exome AF: 0.000821

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00854

Gnomad NFE exome AF: 0.000623

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.00108 AC: 592 AN: 548096 Hom.: 2 Cov.: 0 AF XY: 0.000991 AC XY: 294 AN XY: 296794

African (AFR) AF: 0.000254 AC: 4 AN: 15734

American (AMR) AF: 0.000634 AC: 22 AN: 34708

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20026

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.000431 AC: 27 AN: 62682

European-Finnish (FIN) AF: 0.00889 AC: 295 AN: 33194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2444

European-Non Finnish (NFE) AF: 0.000676 AC: 214 AN: 316790

Other (OTH) AF: 0.000986 AC: 30 AN: 30414

GnomAD4 genome AF: 0.00150 AC: 228 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.00175 AC XY: 130 AN XY: 74478

African (AFR) AF: 0.0000962 AC: 4 AN: 41582

American (AMR) AF: 0.00137 AC: 21 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000882 AC: 60 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000395 Hom.: 0

Bravo AF: 0.00100

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Metaphyseal chondrodysplasia, McKusick type (10)
5	-	-	not provided (5)
2	-	-	Metaphyseal dysplasia without hypotrichosis (2)
1	-	-	Anauxetic dysplasia (1)
1	-	-	Metaphyseal chondrodysplasia, McKusick type;C1834821:Metaphyseal dysplasia without hypotrichosis;C4551965:Anauxetic dysplasia 1 (1)
1	-	-	RMRP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.15
CADD	Benign	19
DANN	Benign	0.91
PhyloP100		7.2
PromoterAI		0.021	Neutral

Splicing

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

Other links and lift over

dbSNP: rs199476103; hg19: chr9-35657945;