12-123256945-C-T

Variant names:

• chr12-123256945-C-T
• rs398122365
• NM_152269.5:c.415C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_152269.5(MTRFR):​c.415C>T​(p.Gln139*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MTRFR NM_152269.5 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.79
• Publications: 1 publications found

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

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.172 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-123256945-C-T is Pathogenic according to our data. Variant chr12-123256945-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 88864.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152269.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRFR	NM_152269.5	MANE Select	c.415C>T	p.Gln139*	stop_gained	Exon 3 of 3	NP_689482.1
	MTRFR	NM_001143905.2		c.415C>T	p.Gln139*	stop_gained	Exon 3 of 3	NP_001137377.1
	MTRFR	NM_001194995.1		c.415C>T	p.Gln139*	stop_gained	Exon 3 of 3	NP_001181924.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRFR	ENST00000253233.6	TSL:1 MANE Select	c.415C>T	p.Gln139*	stop_gained	Exon 3 of 3	ENSP00000253233.1
	MTRFR	ENST00000366329.7	TSL:2	c.415C>T	p.Gln139*	stop_gained	Exon 3 of 3	ENSP00000390647.1
	MTRFR	ENST00000429587.2	TSL:2	c.415C>T	p.Gln139*	stop_gained	Exon 2 of 2	ENSP00000391513.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Hereditary spastic paraplegia 55 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		5.8
Vest4		0.32
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs398122365; hg19: chr12-123741492;