12-123253706-C-T

Position:

chr12-123253706-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152269.5(MTRFR):c.32C>T(p.Thr11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

MTRFR
NM_152269.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.522

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04045883).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MTRFR	NM_152269.5 linkuse as main transcript	c.32C>T	p.Thr11Ile	missense_variant	2/3	ENST00000253233.6	NP_689482.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MTRFR	ENST00000253233.6 linkuse as main transcript	c.32C>T	p.Thr11Ile	missense_variant	2/3	1	NM_152269.5	ENSP00000253233	P1	Q9H3J6-1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000289

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251448

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.000289

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 16, 2021

This sequence change replaces threonine with isoleucine at codon 11 of the C12orf65 protein (p.Thr11Ile). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs143410718, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with C12orf65-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.52

CADD

Benign

0.89

DANN

Benign

0.96

DEOGEN2

Benign

0.011

T;.;.;T;T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.42

.;T;T;T;T;.

M_CAP

Benign

0.0061

MetaRNN

Benign

0.040

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;.;N;.;N

MutationTaster

Benign

1.0

N;N;N

PROVEAN

Benign

-0.34

N;D;N;N;N;N

REVEL

Benign

0.050

Sift

Benign

0.23

T;T;T;T;T;T

Sift4G

Benign

0.49

T;D;T;T;T;T

Polyphen

0.0030

B;.;.;B;.;B

Vest4

0.15

MVP

0.088

MPC

0.048

ClinPred

0.0093

GERP RS

1.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.021

gMVP

0.38

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