rs2280424

Variant names:

• chr12-123253947-C-T
• rs2280424
• NM_152269.5:c.273C>T
• MTRFR p.Ile91Ile

Your query was ambiguous. Multiple possible variants found:

• chr12-123253947-C-T
• chr12-123253947-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_152269.5(MTRFR):​c.273C>T​(p.Ile91Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.044 in 1,614,058 control chromosomes in the GnomAD database, including 2,622 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (308 hom., cov: 31)
  • Exomes 𝑓: 0.044 (2314 hom.)
• Consequence: MTRFR NM_152269.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.150
• Publications: 15 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 12-123253947-C-T is Benign according to our data. Variant chr12-123253947-C-T is described in ClinVar as Benign. ClinVar VariationId is 262628.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRFR	NM_152269.5	MANE Select	c.273C>T	p.Ile91Ile	synonymous	Exon 2 of 3	NP_689482.1	Q9H3J6-1
	MTRFR	NM_001143905.2		c.273C>T	p.Ile91Ile	synonymous	Exon 2 of 3	NP_001137377.1	Q9H3J6-1
	MTRFR	NM_001194995.1		c.273C>T	p.Ile91Ile	synonymous	Exon 2 of 3	NP_001181924.1	Q9H3J6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRFR	ENST00000253233.6	TSL:1 MANE Select	c.273C>T	p.Ile91Ile	synonymous	Exon 2 of 3	ENSP00000253233.1	Q9H3J6-1
	MTRFR	ENST00000366329.7	TSL:2	c.273C>T	p.Ile91Ile	synonymous	Exon 2 of 3	ENSP00000390647.1	Q9H3J6-1
	MTRFR	ENST00000429587.2	TSL:2	c.273C>T	p.Ile91Ile	synonymous	Exon 1 of 2	ENSP00000391513.2	Q9H3J6-1

Frequencies

GnomAD3 genomes AF: 0.0480 AC: 7309 AN: 152122 Hom.: 308 Cov.: 31

Gnomad AFR AF: 0.0432

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0551

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.0491

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0369

Gnomad OTH AF: 0.0589

GnomAD2 exomes AF: 0.0574 AC: 14339 AN: 249938 AF XY: 0.0557

Gnomad AFR exome AF: 0.0441

Gnomad AMR exome AF: 0.0627

Gnomad ASJ exome AF: 0.0366

Gnomad EAS exome AF: 0.262

Gnomad FIN exome AF: 0.0265

Gnomad NFE exome AF: 0.0368

Gnomad OTH exome AF: 0.0493

GnomAD4 exome AF: 0.0436 AC: 63741 AN: 1461818 Hom.: 2314 Cov.: 31 AF XY: 0.0438 AC XY: 31856 AN XY: 727202

African (AFR) AF: 0.0437 AC: 1464 AN: 33480

American (AMR) AF: 0.0633 AC: 2832 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 971 AN: 26136

East Asian (EAS) AF: 0.247 AC: 9792 AN: 39696

South Asian (SAS) AF: 0.0437 AC: 3771 AN: 86252

European-Finnish (FIN) AF: 0.0278 AC: 1486 AN: 53390

Middle Eastern (MID) AF: 0.0463 AC: 267 AN: 5762

European-Non Finnish (NFE) AF: 0.0360 AC: 40020 AN: 1111990

Other (OTH) AF: 0.0520 AC: 3138 AN: 60390

GnomAD4 genome AF: 0.0480 AC: 7312 AN: 152240 Hom.: 308 Cov.: 31 AF XY: 0.0491 AC XY: 3655 AN XY: 74442

African (AFR) AF: 0.0433 AC: 1798 AN: 41538

American (AMR) AF: 0.0550 AC: 841 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.256 AC: 1318 AN: 5158

South Asian (SAS) AF: 0.0489 AC: 236 AN: 4824

European-Finnish (FIN) AF: 0.0251 AC: 266 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0369 AC: 2512 AN: 68016

Other (OTH) AF: 0.0587 AC: 124 AN: 2112

Alfa AF: 0.0439 Hom.: 356

Bravo AF: 0.0534

Asia WGS AF: 0.148 AC: 511 AN: 3478

EpiCase AF: 0.0365

EpiControl AF: 0.0373

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Combined oxidative phosphorylation defect type 7 (1)
-	-	1	not specified (1)
-	-	1	Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.28
CADD	Benign	9.8
DANN	Benign	0.74
PhyloP100		-0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2280424;

hg19: chr12-123738494;

COSMIC: COSV53515771;

COSMIC: COSV53515771;