12-123253947-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_152269.5(MTRFR):c.273C>T(p.Ile91Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,614,058 control chromosomes in the GnomAD database, including 2,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.048 ( 308 hom., cov: 31)

Exomes 𝑓: 0.044 ( 2314 hom. )

Consequence

MTRFR
NM_152269.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.150

Publications

15 publications found

Variant links:

Genes affected

MTRFR (HGNC:26784): (mitochondrial translation release factor in rescue) This nuclear gene encodes a mitochondrial matrix protein that appears to contribute to peptide chain termination in the mitochondrial translation machinery. Two different 1 bp deletions (resulting in the same premature stop codon)result in decreased mitochondrial translation, decreased levels of oxidative phosphorylation complexes and encepthalomyopathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

MTRFR links:

CDK2AP1 (HGNC:14002): (cyclin dependent kinase 2 associated protein 1) The protein encoded by this gene is a cyclin-dependent kinase 2 (CDK2) -associated protein which is thought to negatively regulate CDK2 activity by sequestering monomeric CDK2, and targeting CDK2 for proteolysis. This protein was found to also interact with DNA polymerase alpha/primase and mediate the phosphorylation of the large p180 subunit, which suggests a regulatory role in DNA replication during the S-phase of the cell cycle. This protein also forms a core subunit of the nucleosome remodeling and histone deacetylation (NURD) complex that epigenetically regulates embryonic stem cell differentiation. This gene thus plays a role in both cell-cycle and epigenetic regulation. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2012]

CDK2AP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP6

Variant 12-123253947-C-T is Benign according to our data. Variant chr12-123253947-C-T is described in ClinVar as [Benign]. Clinvar id is 262628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.15 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MTRFR	NM_152269.5 link	c.273C>T	p.Ile91Ile	synonymous_variant	Exon 2 of 3	ENST00000253233.6	NP_689482.1	Q9H3J6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MTRFR	ENST00000253233.6 link	c.273C>T	p.Ile91Ile	synonymous_variant	Exon 2 of 3	1	NM_152269.5	ENSP00000253233.1		Q9H3J6-1

Frequencies

GnomAD3 genomes

AF:

0.0480

AC:

7309

AN:

152122

Hom.:

308

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0432

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.255

Gnomad SAS

AF:

0.0491

Gnomad FIN

AF:

0.0251

Gnomad MID

AF:

0.0475

Gnomad NFE

AF:

0.0369

Gnomad OTH

AF:

0.0589

GnomAD2 exomes

AF:

0.0574

AC:

14339

AN:

249938

AF XY:

0.0557

show subpopulations

Gnomad AFR exome

AF:

0.0441

Gnomad AMR exome

AF:

0.0627

Gnomad ASJ exome

AF:

0.0366

Gnomad EAS exome

AF:

0.262

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0368

Gnomad OTH exome

AF:

0.0493

GnomAD4 exome

AF:

0.0436

AC:

63741

AN:

1461818

Hom.:

2314

Cov.:

AF XY:

0.0438

AC XY:

31856

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0437

AC:

1464

AN:

33480

American (AMR)

AF:

0.0633

AC:

2832

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

971

AN:

26136

East Asian (EAS)

AF:

0.247

AC:

9792

AN:

39696

South Asian (SAS)

AF:

0.0437

AC:

3771

AN:

86252

European-Finnish (FIN)

AF:

0.0278

AC:

1486

AN:

53390

Middle Eastern (MID)

AF:

0.0463

AC:

267

AN:

5762

European-Non Finnish (NFE)

AF:

0.0360

AC:

40020

AN:

1111990

Other (OTH)

AF:

0.0520

AC:

3138

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

3349

6699

10048

13398

16747

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1646

3292

4938

6584

8230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0480

AC:

7312

AN:

152240

Hom.:

308

Cov.:

AF XY:

0.0491

AC XY:

3655

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0433

AC:

1798

AN:

41538

American (AMR)

AF:

0.0550

AC:

841

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3472

East Asian (EAS)

AF:

0.256

AC:

1318

AN:

5158

South Asian (SAS)

AF:

0.0489

AC:

236

AN:

4824

European-Finnish (FIN)

AF:

0.0251

AC:

266

AN:

10618

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0369

AC:

2512

AN:

68016

Other (OTH)

AF:

0.0587

AC:

124

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

345

690

1036

1381

1726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0439

Hom.:

356

Bravo

AF:

0.0534

Asia WGS

AF:

0.148

AC:

511

AN:

3478

EpiCase

AF:

0.0365

EpiControl

AF:

0.0373

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 25, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Combined oxidative phosphorylation defect type 7

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

9.8

(source)

DANN

Benign

0.74

PhyloP100

-0.15

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over