12-123253386-G-T

Position:

• chr12-123253386-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152269.5(MTRFR):​c.-28-261G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0805 in 398,792 control chromosomes in the GnomAD database, including 1,927 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.073 (645 hom., cov: 30)
  • Exomes 𝑓: 0.085 (1282 hom.)
• Consequence: MTRFR NM_152269.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.132

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 (BayesDel_noAF=-0.69).
• BP6: Variant 12-123253386-G-T is Benign according to our data. Variant chr12-123253386-G-T is described in ClinVar as [Benign]. Clinvar id is 680559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRFR	NM_152269.5	c.-28-261G>T		intron_variant		ENST00000253233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRFR	ENST00000253233.6	c.-28-261G>T		intron_variant		1	NM_152269.5	P1

Frequencies

GnomAD3 genomes AF: 0.0734 AC: 11125 AN: 151608 Hom.: 645 Cov.: 30

Gnomad AFR AF: 0.0174

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.0399

Gnomad ASJ AF: 0.0329

Gnomad EAS AF: 0.000969

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.142

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.116

Gnomad OTH AF: 0.0495

GnomAD4 exome AF: 0.0848 AC: 20961 AN: 247066 Hom.: 1282 Cov.: 2 AF XY: 0.0777 AC XY: 10388 AN XY: 133648

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.0312

Gnomad4 ASJ exome AF: 0.0383

Gnomad4 EAS exome AF: 0.000905

Gnomad4 SAS exome AF: 0.0250

Gnomad4 FIN exome AF: 0.148

Gnomad4 NFE exome AF: 0.116

Gnomad4 OTH exome AF: 0.0813

GnomAD4 genome AF: 0.0733 AC: 11127 AN: 151726 Hom.: 645 Cov.: 30 AF XY: 0.0709 AC XY: 5255 AN XY: 74106

Gnomad4 AFR AF: 0.0174

Gnomad4 AMR AF: 0.0399

Gnomad4 ASJ AF: 0.0329

Gnomad4 EAS AF: 0.000971

Gnomad4 SAS AF: 0.0221

Gnomad4 FIN AF: 0.142

Gnomad4 NFE AF: 0.116

Gnomad4 OTH AF: 0.0490

Alfa AF: 0.0677 Hom.: 104

Bravo AF: 0.0634

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	3.3
DANN	Benign	0.65

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: rs76582395; hg19: chr12-123737933;