rs267606618

Positions:

• chrM-1095-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The ENST00000389680.2(MT-RNR1):​n.448T>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as drug response (★★★).

• Frequency: Mitomap GenBank: 𝑓 0.0011 (AC: 65)
• Consequence: MT-RNR1 ENST00000389680.2 non_coding_transcript_exon
• Clinical Significance: drug response reviewed by expert panel P:3 U:1 O:4 SNHL
• Conservation: PhyloP100: 2.56

Genes affected

MT-RNR1 (HGNC:7470): (mitochondrially encoded 12S RNA) Enables DNA binding activity and DNA-binding transcription factor binding activity. Involved in several processes, including osteoblast proliferation; regulation of carbohydrate utilization; and regulation of phosphate metabolic process. Located in extracellular space; mitochondrion; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

RNR1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomadMitoHomoplasmic at 21

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNR1	RNR1.1	n.448T>C		non_coding_transcript_exon_variant	1/1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MT-RNR1	ENST00000389680.2	n.448T>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD4 exome Cov.: 0

We have no GnomAD4 genomes data on this position. Probably position not covered by the project.

Mitomap GenBank AF: 0.0011 AC: 65

Gnomad homoplasmic AF: 0.00037 AC: 21 AN: 56428

Gnomad heteroplasmic AF: 0.000018 AC: 1 AN: 56428

Mitomap

SNHL

ClinVar

Significance: drug response

Submissions summary: Pathogenic:3 Uncertain:1 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

Auditory neuropathy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 26, 2008

- -

Mitochondrial non-syndromic sensorineural hearing loss Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 26, 2008

- -

Aminoglycoside-induced deafness Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 26, 2008

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 04, 2019

The m.1095T>C variant has been reported in 24/2455 individuals with hearing loss, with and without aminoglycoside exposure (Thyagarajan 2000, Tessa 2001, Zhao 2004, Wang 2005, Li 2005, Dai 2006, Lu 2010, Shen 2001). In one Italian family with Parkinsonism, deafness and neuropathy, the variant segregated with hearing loss in at least two additional maternally related family members (Thyagaragan 2000), while in another family the variant segregated with nonsyndromic hearing loss in 4 family members (Tessa 2001), though alternate dominant inheritance cannot be ruled out. In addition, two functional studies show that the m.1095T>C variant impacts function (Thyagarajan 2000, Muderman 2012). Furthermore, a meta-analysis from several studies of mitochondrial hearing loss variants detected in hearing loss cohorts suggests that the m.1095T>C variant has a significant association with hearing loss when aminoglycoside exposure was assessed. However, this variant is reported in 0.12% (58/47,412) individuals in a broad population database (https://www.mitomap.org), and was a defining variant of the M11 haplogroup where it is present in 100% of individuals of that haplogroup (Tanaka 2004, Yao 2006). In summary, there is some evidence suggesting that the m.1095T>C variant may be associated with hearing loss, particularly with aminoglycoside exposure, however because of its frequency in the general population and the M11 haplogroup, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied: PS4_Moderate, PP1, PS3_Supporting, BS1_Supporting. -

gentamicin response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jun 15, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

aminoglycoside antibacterials response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jun 15, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

kanamycin response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jun 15, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

streptomycin response - Toxicity Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Jun 15, 2021

PharmGKB Level of Evidence 1A: Level 1A clinical annotations describe variant-drug combinations that have variant-specific prescribing guidance available in a current clinical guideline annotation or an FDA-approved drug label annotation. Annotations of drug labels or clinical guidelines must give prescribing guidance for specific variants (e.g. CYP2C9*3, HLA-B*57:01) or provide mapping from defined allele functions to diplotypes and phenotypes to be used as supporting evidence for a level 1A clinical annotation. Level 1A clinical annotations must also be supported by at least one publication in addition to a clinical guideline or drug label with variant-specific prescribing guidance. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606618; hg19: chrM-1097;