12-123253947-C-T

Position:

chr12-123253947-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_152269.5(MTRFR):c.273C>T(p.Ile91=) 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

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 made for transcript

Verdict is Benign. Variant got -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/exons	MANE	UniProt
MTRFR	NM_152269.5 linkuse as main transcript	c.273C>T	p.Ile91=	synonymous_variant	2/3	ENST00000253233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRFR	ENST00000253233.6 linkuse as main transcript	c.273C>T	p.Ile91=	synonymous_variant	2/3	1	NM_152269.5	P1	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

GnomAD3 exomes

AF:

0.0574

AC:

14339

AN:

249938

Hom.:

856

AF XY:

0.0557

AC XY:

7556

AN XY:

135564

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 SAS exome

AF:

0.0418

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

Gnomad4 AFR exome

AF:

0.0437

Gnomad4 AMR exome

AF:

0.0633

Gnomad4 ASJ exome

AF:

0.0372

Gnomad4 EAS exome

AF:

0.247

Gnomad4 SAS exome

AF:

0.0437

Gnomad4 FIN exome

AF:

0.0278

Gnomad4 NFE exome

AF:

0.0360

Gnomad4 OTH exome

AF:

0.0520

GnomAD4 genome

AF:

0.0480

AC:

7312

AN:

152240

Hom.:

308

Cov.:

AF XY:

0.0491

AC XY:

3655

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0433

Gnomad4 AMR

AF:

0.0550

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.256

Gnomad4 SAS

AF:

0.0489

Gnomad4 FIN

AF:

0.0251

Gnomad4 NFE

AF:

0.0369

Gnomad4 OTH

AF:

0.0587

Alfa

AF:

0.0418

Hom.:

226

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

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 25, 2016	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Combined oxidative phosphorylation defect type 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

DANN

Benign

0.74

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over