9-35658038-G-C

Variant names:

• chr9-35658038-G-C
• rs183974004
• ENST00000363046.2:n.-19C>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NR_003051.4(RMRP):​n.-19C>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 671,728 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0049 (7 hom., cov: 34)
  • Exomes 𝑓: 0.0027 (5 hom.)
• Consequence: RMRP NR_003051.4 upstream_gene
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.23
• 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 9-35658038-G-C is Benign according to our data. Variant chr9-35658038-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 533769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.-19C>G		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.-19C>G		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00478 AC: 728 AN: 152188 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.00984

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00221 AC: 262 AN: 118506 AF XY: 0.00199

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.000432

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.00219

GnomAD4 exome AF: 0.00267 AC: 1387 AN: 519422 Hom.: 5 Cov.: 0 AF XY: 0.00242 AC XY: 672 AN XY: 277790

African (AFR) AF: 0.0123 AC: 184 AN: 14944

American (AMR) AF: 0.00138 AC: 44 AN: 31862

Ashkenazi Jewish (ASJ) AF: 0.000264 AC: 5 AN: 18920

East Asian (EAS) AF: 0.0000318 AC: 1 AN: 31484

South Asian (SAS) AF: 0.000165 AC: 10 AN: 60518

European-Finnish (FIN) AF: 0.0120 AC: 393 AN: 32792

Middle Eastern (MID) AF: 0.00171 AC: 4 AN: 2336

European-Non Finnish (NFE) AF: 0.00218 AC: 649 AN: 297558

Other (OTH) AF: 0.00334 AC: 97 AN: 29008

GnomAD4 genome AF: 0.00490 AC: 746 AN: 152306 Hom.: 7 Cov.: 34 AF XY: 0.00537 AC XY: 400 AN XY: 74488

African (AFR) AF: 0.0103 AC: 428 AN: 41582

American (AMR) AF: 0.00288 AC: 44 AN: 15298

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

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

European-Finnish (FIN) AF: 0.0101 AC: 107 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68008

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00115 Hom.: 1

Bravo AF: 0.00441

Asia WGS AF: 0.00722 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Anauxetic dysplasia (1)
-	-	1	Metaphyseal chondrodysplasia, McKusick type (1)
-	-	1	not specified (1)
-	-	1	RMRP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.026
DANN	Benign	0.47
PhyloP100		-2.2
PromoterAI		0.042	Neutral

Splicing

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

Other links and lift over

dbSNP: rs183974004; hg19: chr9-35658035;