rs753829320

Variant names:

• chr2-227355756-C-T
• rs753829320
• NM_001277062.2:c.739C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The ENST00000304593.14(MFF):​c.739C>T​(p.Arg247*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000348 in 1,435,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: MFF ENST00000304593.14 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.52
• Publications: 4 publications found

Genes affected

MFF (HGNC:24858): (mitochondrial fission factor) This is a nuclear gene encoding a protein that functions in mitochondrial and peroxisomal fission. The encoded protein recruits dynamin-1-like protein (DNM1L) to mitochondria. There are multiple pseudogenes for this gene on chromosomes 1, 5, and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

MFF Gene-Disease associations (from GenCC):

• encephalopathy due to defective mitochondrial and peroxisomal fission 2

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• encephalopathy due to mitochondrial and peroxisomal fission defect

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.156 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-227355756-C-T is Pathogenic according to our data. Variant chr2-227355756-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 253269.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000304593.14. 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
	MFF	NM_001277062.2	MANE Select	c.739C>T	p.Arg247*	stop_gained	Exon 8 of 9	NP_001263991.1
	MFF	NM_001277061.2		c.892C>T	p.Arg298*	stop_gained	Exon 10 of 11	NP_001263990.1
	MFF	NM_020194.5		c.892C>T	p.Arg298*	stop_gained	Exon 10 of 11	NP_064579.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFF	ENST00000304593.14	TSL:2 MANE Select	c.739C>T	p.Arg247*	stop_gained	Exon 8 of 9	ENSP00000304898.10
	MFF	ENST00000337110.11	TSL:1	c.595C>T	p.Arg199*	stop_gained	Exon 7 of 8	ENSP00000338412.7
	MFF	ENST00000353339.8	TSL:5	c.892C>T	p.Arg298*	stop_gained	Exon 10 of 11	ENSP00000302037.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000348 AC: 5 AN: 1435276 Hom.: 0 Cov.: 26 AF XY: 0.00000419 AC XY: 3 AN XY: 715836

African (AFR) AF: 0.00 AC: 0 AN: 32946

American (AMR) AF: 0.00 AC: 0 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25926

East Asian (EAS) AF: 0.00 AC: 0 AN: 39470

South Asian (SAS) AF: 0.00 AC: 0 AN: 85518

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1088420

Other (OTH) AF: 0.00 AC: 0 AN: 59410

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Encephalopathy due to defective mitochondrial and peroxisomal fission 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		1.5
Vest4		0.97
GERP RS		6.1
Mutation Taster		=0/200	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: rs753829320; hg19: chr2-228220472; COSMIC: COSV58825753;