rs78651634

chr12-123253718-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.627

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]

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]

ACMG classification

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 GnomAd at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRFR	NM_152269.5	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	c.44G>A	p.Arg15Gln	missense_variant	2/3	1	NM_152269.5	P1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2654 AN: 152092 Hom.: 41 Cov.: 31

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.: 67 AF XY: 0.0192 AC XY: 2615 AN XY: 135896

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.: 31 AF XY: 0.0215 AC XY: 15656 AN XY: 727240

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.: 41 Cov.: 31 AF XY: 0.0167 AC XY: 1245 AN XY: 74420

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.: 69

Bravo AF: 0.0182

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0269 AC: 231

ExAC AF: 0.0194 AC: 2352

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0284

EpiControl AF: 0.0302

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 15, 2021

- -

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 08, 2016

- -

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
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	N
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
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	T
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

Other links and lift over

dbSNP: rs78651634; hg19: chr12-123738265;