17-36602081-A-G

Variant names:

• chr17-36602081-A-G
• rs759984768
• NM_024864.5:c.271A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024864.5(MRM1):​c.271A>G​(p.Met91Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,458,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: MRM1 NM_024864.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.691
• Publications: 0 publications found

Genes affected

MRM1 (HGNC:26202): (mitochondrial rRNA methyltransferase 1) Enables rRNA (guanosine-2'-O-)-methyltransferase activity. Predicted to be involved in rRNA 2'-O-methylation. Located in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052734226).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRM1	NM_024864.5	c.271A>G	p.Met91Val	missense_variant	Exon 1 of 5	ENST00000614766.5	NP_079140.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRM1	ENST00000614766.5	c.271A>G	p.Met91Val	missense_variant	Exon 1 of 5	1	NM_024864.5	ENSP00000481559.1
MRM1	ENST00000612760.1	c.-139A>G		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000482526.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 244190 AF XY: 0.00000750

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000906

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1458382 Hom.: 0 Cov.: 31 AF XY: 0.0000358 AC XY: 26 AN XY: 725680

African (AFR) AF: 0.0000299 AC: 1 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50430

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111636

Other (OTH) AF: 0.0000166 AC: 1 AN: 60350

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000825 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.271A>G (p.M91V) alteration is located in exon 1 (coding exon 1) of the MRM1 gene. This alteration results from a A to G substitution at nucleotide position 271, causing the methionine (M) at amino acid position 91 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.81
DANN	Benign	0.42
DEOGEN2	Benign	0.026	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.016	N
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.053	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.69
PrimateAI	Uncertain	0.63	T
Sift4G	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.48		Loss of disorder (P = 0.0915);
MVP		0.11
ClinPred		0.024	T
GERP RS		1.8
PromoterAI		-0.046	Neutral
Varity_R		0.044
gMVP		0.39
Mutation Taster		=281/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs759984768; hg19: chr17-34958510;