6-41649637-C-G

Variant names:

• chr6-41649637-C-G
• NM_005586.4:c.278C>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005586.4(MDFI):​c.278C>G​(p.Pro93Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MDFI NM_005586.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53

Genes affected

MDFI (HGNC:6967): (MyoD family inhibitor) This protein is a transcription factor that negatively regulates other myogenic family proteins. Studies of the mouse homolog, I-mf, show that it interferes with myogenic factor function by masking nuclear localization signals and preventing DNA binding. Knockout mouse studies show defects in the formation of vertebrae and ribs that also involve cartilage formation in these structures. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3573925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDFI	NM_005586.4	c.278C>G	p.Pro93Arg	missense_variant	Exon 4 of 5	ENST00000230321.11	NP_005577.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDFI	ENST00000230321.11	c.278C>G	p.Pro93Arg	missense_variant	Exon 4 of 5	1	NM_005586.4	ENSP00000230321.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.278C>G (p.P93R) alteration is located in exon 4 (coding exon 3) of the MDFI gene. This alteration results from a C to G substitution at nucleotide position 278, causing the proline (P) at amino acid position 93 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;.;D;.;D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;T;.;T;T;T;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.3	.;.;M;.;M;.;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.2	D;D;D;D;D;N;D;N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;D;D;D;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;T;D;T
Polyphen		1.0	.;.;D;.;D;.;.;.
Vest4		0.28, 0.28, 0.29
MutPred		0.42		Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);Gain of solvent accessibility (P = 0.008);.;Gain of solvent accessibility (P = 0.008);.;
MVP		0.66
MPC		0.76
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.56

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-41617375;