12-123253718-G-A

Position:

chr12-123253718-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_152269.5(MTRFR):c.44G>A(p.Arg15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,092 control chromosomes in the GnomAD database, including 465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.017 ( 41 hom., cov: 31)

Exomes 𝑓: 0.022 ( 424 hom. )

Consequence

MTRFR
NM_152269.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.627

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0036120713).

BP6

Variant 12-123253718-G-A is Benign according to our data. Variant chr12-123253718-G-A is described in ClinVar as [Benign]. Clinvar id is 128535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123253718-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0174 (2654/152210) while in subpopulation NFE AF= 0.0271 (1842/68000). AF 95% confidence interval is 0.0261. There are 41 homozygotes in gnomad4. There are 1245 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRFR	NM_152269.5 linkuse as main transcript	c.44G>A	p.Arg15Gln	missense_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.44G>A	p.Arg15Gln	missense_variant	2/3	1	NM_152269.5	P1	Q9H3J6-1

Frequencies

GnomAD3 genomes

AF:

0.0175

AC:

2654

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00459

Gnomad AMI

AF:

0.0197

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.00556

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0230

GnomAD3 exomes

AF:

0.0189

AC:

4745

AN:

251430

Hom.:

AF XY:

0.0192

AC XY:

2615

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.00357

Gnomad AMR exome

AF:

0.0205

Gnomad ASJ exome

AF:

0.0301

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00643

Gnomad FIN exome

AF:

0.00642

Gnomad NFE exome

AF:

0.0278

Gnomad OTH exome

AF:

0.0282

GnomAD4 exome

AF:

0.0218

AC:

31863

AN:

1461882

Hom.:

424

Cov.:

AF XY:

0.0215

AC XY:

15656

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00355

Gnomad4 AMR exome

AF:

0.0206

Gnomad4 ASJ exome

AF:

0.0343

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00752

Gnomad4 FIN exome

AF:

0.00797

Gnomad4 NFE exome

AF:

0.0246

Gnomad4 OTH exome

AF:

0.0219

GnomAD4 genome

AF:

0.0174

AC:

2654

AN:

152210

Hom.:

Cov.:

AF XY:

0.0167

AC XY:

1245

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00457

Gnomad4 AMR

AF:

0.0234

Gnomad4 ASJ

AF:

0.0311

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00477

Gnomad4 FIN

AF:

0.00556

Gnomad4 NFE

AF:

0.0271

Gnomad4 OTH

AF:

0.0227

Alfa

AF:

0.0242

Hom.:

Bravo

AF:

0.0182

TwinsUK

AF:

0.0202

AC:

ALSPAC

AF:

0.0218

AC:

ESP6500AA

AF:

0.00431

AC:

ESP6500EA

AF:

0.0269

AC:

231

ExAC

AF:

0.0194

AC:

2352

Asia WGS

AF:

0.00346

AC:

AN:

3478

EpiCase

AF:

0.0284

EpiControl

AF:

0.0302

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -

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

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 15, 2021

- -

Combined oxidative phosphorylation defect type 7

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

T;.;.;T;T;T

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.72

.;T;T;T;T;.

MetaRNN

Benign

0.0036

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.;M;.;M

MutationTaster

Benign

1.0

N;N;N

PROVEAN

Benign

-1.3

N;D;N;N;N;N

REVEL

Benign

0.093

Sift

Uncertain

0.013

D;D;D;D;D;D

Sift4G

Uncertain

0.016

D;D;D;D;D;D

Polyphen

0.92

P;.;.;P;.;P

Vest4

0.25

MPC

0.22

ClinPred

0.019

GERP RS

4.7

Varity_R

0.053

gMVP

0.51

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

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