Genetic Variant MDFI:p.His43Gln (chr6-41646178-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_005586.4(MDFI):c.129C>A(p.His43Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000239 in 1,588,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000077 ( 0 hom. )

Consequence

MDFI
NM_005586.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.52

Variant links:

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]

MDFI links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.043908626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDFI	NM_005586.4 link	c.129C>A	p.His43Gln	missense_variant	Exon 3 of 5	ENST00000230321.11	NP_005577.1	Q99750A0A024RCY2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDFI	ENST00000230321.11 link	c.129C>A	p.His43Gln	missense_variant	Exon 3 of 5	1	NM_005586.4	ENSP00000230321.6		Q99750

Frequencies

GnomAD3 genomes

AF:

0.000177

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000873

AC:

AN:

229120

Hom.:

AF XY:

0.0000161

AC XY:

AN XY:

124214

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000666

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000766

AC:

AN:

1436032

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

713850

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000196

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000273

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000177

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.000374

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 18, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.129C>A (p.H43Q) alteration is located in exon 3 (coding exon 2) of the MDFI gene. This alteration results from a C to A substitution at nucleotide position 129, causing the histidine (H) at amino acid position 43 to be replaced by a glutamine (Q). 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

0.088

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.47

CADD

Benign

7.8

DANN

Uncertain

0.97

DEOGEN2

Benign

0.23

.;.;T;.;T;.

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.43

T;T;.;T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.044

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;.;L;.;L;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-1.2

N;N;N;D;N;D

REVEL

Benign

0.077

Sift

Uncertain

0.016

D;D;D;D;D;D

Sift4G

Benign

0.59

T;T;T;D;T;D

Polyphen

0.0

.;.;B;.;B;.

Vest4

0.14, 0.14

MutPred

0.33

Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);Loss of sheet (P = 0.1398);

MVP

0.73

MPC

0.22

ClinPred

0.15

GERP RS

2.5

Varity_R

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over