rs78651634

Variant names:

• chr12-123253718-G-A
• rs78651634
• NM_152269.5:c.44G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-123253718-G-A
• chr12-123253718-G-C
• chr12-123253718-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_152269.5(MTRFR):​c.44G>A​(p.Arg15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,614,092 control chromosomes in the GnomAD database, including 465 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (41 hom., cov: 31)
  • Exomes 𝑓: 0.022 (424 hom.)
• Consequence: MTRFR NM_152269.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.627
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0036120713).
• BP6: Variant 12-123253718-G-A is Benign according to our data. Variant chr12-123253718-G-A is described in ClinVar as Benign. ClinVar VariationId is 128535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0174 (2654/152210) while in subpopulation NFE AF = 0.0271 (1842/68000). AF 95% confidence interval is 0.0261. There are 41 homozygotes in GnomAd4. There are 1245 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

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.44G>A	p.Arg15Gln	missense	Exon 2 of 3	NP_689482.1
	MTRFR	NM_001143905.2		c.44G>A	p.Arg15Gln	missense	Exon 2 of 3	NP_001137377.1
	MTRFR	NM_001194995.1		c.44G>A	p.Arg15Gln	missense	Exon 2 of 3	NP_001181924.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MTRFR	ENST00000253233.6	TSL:1 MANE Select	c.44G>A	p.Arg15Gln	missense	Exon 2 of 3	ENSP00000253233.1
	MTRFR	ENST00000366329.7	TSL:2	c.44G>A	p.Arg15Gln	missense	Exon 2 of 3	ENSP00000390647.1
	MTRFR	ENST00000429587.2	TSL:2	c.44G>A	p.Arg15Gln	missense	Exon 1 of 2	ENSP00000391513.2

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2654 AN: 152092 Hom.: 41 Cov.: 31

Gnomad AFR AF: 0.00459

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00456

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0230

GnomAD2 exomes AF: 0.0189 AC: 4745 AN: 251430 AF XY: 0.0192

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.0205

Gnomad ASJ exome AF: 0.0301

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00642

Gnomad NFE exome AF: 0.0278

Gnomad OTH exome AF: 0.0282

GnomAD4 exome AF: 0.0218 AC: 31863 AN: 1461882 Hom.: 424 Cov.: 31 AF XY: 0.0215 AC XY: 15656 AN XY: 727240

African (AFR) AF: 0.00355 AC: 119 AN: 33480

American (AMR) AF: 0.0206 AC: 921 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0343 AC: 897 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00752 AC: 649 AN: 86252

European-Finnish (FIN) AF: 0.00797 AC: 426 AN: 53418

Middle Eastern (MID) AF: 0.0248 AC: 143 AN: 5768

European-Non Finnish (NFE) AF: 0.0246 AC: 27380 AN: 1112008

Other (OTH) AF: 0.0219 AC: 1325 AN: 60396

GnomAD4 genome AF: 0.0174 AC: 2654 AN: 152210 Hom.: 41 Cov.: 31 AF XY: 0.0167 AC XY: 1245 AN XY: 74420

African (AFR) AF: 0.00457 AC: 190 AN: 41536

American (AMR) AF: 0.0234 AC: 357 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0311 AC: 108 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5178

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4822

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1842 AN: 68000

Other (OTH) AF: 0.0227 AC: 48 AN: 2110

Alfa AF: 0.0239 Hom.: 165

Bravo AF: 0.0182

TwinsUK AF: 0.0202 AC: 75

ALSPAC AF: 0.0218 AC: 84

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.0269 AC: 231

ExAC AF: 0.0194 AC: 2352

Asia WGS AF: 0.00346 AC: 13 AN: 3478

EpiCase AF: 0.0284

EpiControl AF: 0.0302

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Combined oxidative phosphorylation defect type 7 (1)
-	-	1	Hereditary spastic paraplegia (1)
-	-	1	Spastic paraplegia;C3150801:Combined oxidative phosphorylation defect type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.63
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.093
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.016	D
Polyphen		0.92	P
Vest4		0.25
MPC		0.22
ClinPred		0.019	T
GERP RS		4.7
PromoterAI		-0.010	Neutral
Varity_R		0.053
gMVP		0.51
Mutation Taster		=99/1	polymorphism (auto)

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: rs78651634; hg19: chr12-123738265;