chr17-36602003-G-C

Variant names:

• chr17-36602003-G-C
• rs540283096
• NM_024864.5:c.193G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024864.5(MRM1):​c.193G>C​(p.Ala65Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A65S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRM1 NM_024864.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.395
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.070709735).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRM1	NM_024864.5	c.193G>C	p.Ala65Pro	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.193G>C	p.Ala65Pro	missense_variant	Exon 1 of 5	1	NM_024864.5	ENSP00000481559.1
MRM1	ENST00000612760.1	c.-217G>C		5_prime_UTR_variant	Exon 1 of 5	1		ENSP00000482526.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000204 AC: 48 AN: 234982 AF XY: 0.000171

Gnomad AFR exome AF: 0.000964

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.000104

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.000917

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000200 AC: 29 AN: 1453422 Hom.: 0 Cov.: 31 AF XY: 0.0000277 AC XY: 20 AN XY: 722888

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.0000225 AC: 1 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 85730

European-Finnish (FIN) AF: 0.000450 AC: 22 AN: 48842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5526

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1110038

Other (OTH) AF: 0.0000500 AC: 3 AN: 60050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000744 AC: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.037	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.57	N
PhyloP100		0.40
PrimateAI	Uncertain	0.75	T
Sift4G	Benign	0.28	T
Polyphen		0.49	P
Vest4		0.24
MutPred		0.66		Gain of glycosylation at A65 (P = 0.0257);
MVP		0.41
ClinPred		0.056	T
GERP RS		3.7
PromoterAI		-0.13	Neutral
Varity_R		0.32
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs540283096; hg19: chr17-34958432;