12-123233754-C-T

Position:

• chr12-123233754-C-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.-29+223C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,298 control chromosomes in the GnomAD database, including 30,897 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (30807 hom., cov: 31)
  • Exomes 𝑓: 0.80 (90 hom.)
• Consequence: MTRFR NM_152269.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.613

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]

MPHOSPH9 (HGNC:7215): (M-phase phosphoprotein 9) Located in Golgi apparatus and centriole. Implicated in multiple sclerosis. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-123233754-C-T is Benign according to our data. Variant chr12-123233754-C-T is described in ClinVar as [Benign]. Clinvar id is 671535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MTRFR	NM_152269.5	c.-29+223C>T		intron_variant		ENST00000253233.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MTRFR	ENST00000253233.6	c.-29+223C>T		intron_variant		1	NM_152269.5	P1

Frequencies

GnomAD3 genomes AF: 0.591 AC: 89699 AN: 151900 Hom.: 30806 Cov.: 31

Gnomad AFR AF: 0.214

Gnomad AMI AF: 0.746

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.645

Gnomad EAS AF: 0.726

Gnomad SAS AF: 0.722

Gnomad FIN AF: 0.751

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.749

Gnomad OTH AF: 0.619

GnomAD4 exome AF: 0.800 AC: 224 AN: 280 Hom.: 90 Cov.: 0 AF XY: 0.807 AC XY: 171 AN XY: 212

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.833

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.772

Gnomad4 OTH exome AF: 0.900

GnomAD4 genome AF: 0.590 AC: 89717 AN: 152018 Hom.: 30807 Cov.: 31 AF XY: 0.595 AC XY: 44214 AN XY: 74308

Gnomad4 AFR AF: 0.214

Gnomad4 AMR AF: 0.682

Gnomad4 ASJ AF: 0.645

Gnomad4 EAS AF: 0.726

Gnomad4 SAS AF: 0.722

Gnomad4 FIN AF: 0.751

Gnomad4 NFE AF: 0.749

Gnomad4 OTH AF: 0.623

Alfa AF: 0.657 Hom.: 4343

Bravo AF: 0.563

Asia WGS AF: 0.697 AC: 2424 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 18, 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	-0.78
CADD	Benign	4.8
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1727332; hg19: chr12-123718301;