9-35657891-C-G

Variant names:

• chr9-35657891-C-G
• rs74810894
• ENST00000363046.2:n.129G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP6

The NR_003051.4(RMRP):​n.129G>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00265 in 700,432 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0025 (1 hom.)
• Consequence: RMRP NR_003051.4 non_coding_transcript_exon
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 1.70
• Publications: 1 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-35657891-C-G is Benign according to our data. Variant chr9-35657891-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465201.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	NR_003051.4	MANE Select	n.129G>C		non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RMRP	ENST00000363046.2	TSL:6 MANE Select	n.129G>C		non_coding_transcript_exon	Exon 1 of 1

Frequencies

GnomAD3 genomes AF: 0.00321 AC: 489 AN: 152216 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00538

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00275

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00255 AC: 333 AN: 130502 AF XY: 0.00247

Gnomad AFR exome AF: 0.00427

Gnomad AMR exome AF: 0.00275

Gnomad ASJ exome AF: 0.00839

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00324

Gnomad OTH exome AF: 0.00200

GnomAD4 exome AF: 0.00249 AC: 1367 AN: 548096 Hom.: 1 Cov.: 0 AF XY: 0.00237 AC XY: 703 AN XY: 296794

African (AFR) AF: 0.00528 AC: 83 AN: 15734

American (AMR) AF: 0.00294 AC: 102 AN: 34706

Ashkenazi Jewish (ASJ) AF: 0.00699 AC: 140 AN: 20026

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

South Asian (SAS) AF: 0.000160 AC: 10 AN: 62682

European-Finnish (FIN) AF: 0.000362 AC: 12 AN: 33190

Middle Eastern (MID) AF: 0.00941 AC: 23 AN: 2444

European-Non Finnish (NFE) AF: 0.00281 AC: 890 AN: 316796

Other (OTH) AF: 0.00352 AC: 107 AN: 30414

GnomAD4 genome AF: 0.00321 AC: 489 AN: 152336 Hom.: 1 Cov.: 34 AF XY: 0.00272 AC XY: 203 AN XY: 74496

African (AFR) AF: 0.00536 AC: 223 AN: 41590

American (AMR) AF: 0.00268 AC: 41 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00275 AC: 187 AN: 68020

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00252 Hom.: 0

Bravo AF: 0.00353

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	10
DANN	Benign	0.46
PhyloP100		1.7
PromoterAI		0.10	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs74810894; hg19: chr9-35657888;