2-227356053-T-C

Variant names:

• chr2-227356053-T-C
• rs7560053
• NM_001277062.2:c.744+292T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001277062.2(MFF):​c.744+292T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.679 in 152,122 control chromosomes in the GnomAD database, including 35,331 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.68 (35331 hom., cov: 32)
• Consequence: MFF NM_001277062.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0380
• Publications: 23 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 2-227356053-T-C is Benign according to our data. Variant chr2-227356053-T-C is described in ClinVar as [Benign]. Clinvar id is 684252.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFF	NM_001277062.2	c.744+292T>C		intron_variant	Intron 8 of 8	ENST00000304593.14	NP_001263991.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFF	ENST00000304593.14	c.744+292T>C		intron_variant	Intron 8 of 8	2	NM_001277062.2	ENSP00000304898.10

Frequencies

GnomAD3 genomes AF: 0.679 AC: 103173 AN: 152002 Hom.: 35295 Cov.: 32

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.542

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.653

Gnomad EAS AF: 0.577

Gnomad SAS AF: 0.723

Gnomad FIN AF: 0.652

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.659

Gnomad OTH AF: 0.651

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.679 AC: 103266 AN: 152122 Hom.: 35331 Cov.: 32 AF XY: 0.677 AC XY: 50333 AN XY: 74376

African (AFR) AF: 0.771 AC: 31993 AN: 41516

American (AMR) AF: 0.573 AC: 8758 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.653 AC: 2265 AN: 3466

East Asian (EAS) AF: 0.576 AC: 2978 AN: 5166

South Asian (SAS) AF: 0.723 AC: 3485 AN: 4822

European-Finnish (FIN) AF: 0.652 AC: 6894 AN: 10576

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.659 AC: 44816 AN: 67982

Other (OTH) AF: 0.652 AC: 1379 AN: 2114

Alfa AF: 0.663 Hom.: 106253

Bravo AF: 0.675

Asia WGS AF: 0.643 AC: 2238 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.93
CADD	Benign	14
DANN	Benign	0.75
PhyloP100		-0.038
Mutation Taster		=100/0	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: rs7560053; hg19: chr2-228220769;