7-2235298-C-T

Position:

• chr7-2235298-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_013393.3(MRM2):​c.565G>A​(p.Gly189Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G189E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MRM2 NM_013393.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.43

Genes affected

MRM2 (HGNC:16352): (mitochondrial rRNA methyltransferase 2) The protein encoded by this gene is a member of the S-adenosylmethionine-binding protein family. It is a nucleolar protein and it may be involved in the processing and modification of rRNA. This gene has been suggested to be involved in cell cycle control and DNA repair. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 7-2235298-C-T is Pathogenic according to our data. Variant chr7-2235298-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 689394.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr7-2235298-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRM2	NM_013393.3	c.565G>A	p.Gly189Arg	missense_variant	3/3	ENST00000242257.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRM2	ENST00000242257.14	c.565G>A	p.Gly189Arg	missense_variant	3/3	1	NM_013393.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727220

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Mitochondrial DNA depletion syndrome 17 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	.;D;.
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-6.5	D;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0010	D;.;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.98
MutPred		0.96		Gain of MoRF binding (P = 0.0364);Gain of MoRF binding (P = 0.0364);.;
MVP		0.86
MPC		0.80
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.94
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs1584622847; hg19: chr7-2274933;