rs753464609

Variant names:

• chr6-41646219-C-T
• rs753464609
• NM_005586.4:c.170C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_005586.4(MDFI):​c.170C>T​(p.Ala57Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000282 in 1,593,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: MDFI NM_005586.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -3.08
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045724034).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005586.4. 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
	MDFI	NM_005586.4	MANE Select	c.170C>T	p.Ala57Val	missense	Exon 3 of 5	NP_005577.1	Q99750
	MDFI	NM_001300804.2		c.170C>T	p.Ala57Val	missense	Exon 4 of 6	NP_001287733.1	Q99750
	MDFI	NM_001300806.2		c.170C>T	p.Ala57Val	missense	Exon 2 of 4	NP_001287735.1	Q99750

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDFI	ENST00000230321.11	TSL:1 MANE Select	c.170C>T	p.Ala57Val	missense	Exon 3 of 5	ENSP00000230321.6	Q99750
	MDFI	ENST00000373051.6	TSL:5	c.170C>T	p.Ala57Val	missense	Exon 3 of 5	ENSP00000362142.2	Q99750
	MDFI	ENST00000909785.1		c.170C>T	p.Ala57Val	missense	Exon 3 of 5	ENSP00000579844.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 233142 AF XY: 0.0000158

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000620

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.00000933

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000298 AC: 43 AN: 1440978 Hom.: 0 Cov.: 31 AF XY: 0.0000265 AC XY: 19 AN XY: 716338

African (AFR) AF: 0.00 AC: 0 AN: 32562

American (AMR) AF: 0.0000240 AC: 1 AN: 41632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25636

East Asian (EAS) AF: 0.0000798 AC: 3 AN: 37596

South Asian (SAS) AF: 0.0000362 AC: 3 AN: 82940

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.0000318 AC: 35 AN: 1102086

Other (OTH) AF: 0.0000168 AC: 1 AN: 59618

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	0.059
DANN	Benign	0.96
DEOGEN2	Benign	0.090	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.69	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.046	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.90	L
PhyloP100		-3.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.072
Sift	Benign	0.19	T
Sift4G	Benign	0.26	T
Polyphen		0.0010	B
Vest4		0.083
MutPred		0.18		Gain of catalytic residue at A57 (P = 0.0075)
MVP		0.31
MPC		0.22
ClinPred		0.036	T
GERP RS		-7.4
Varity_R		0.030
Mutation Taster		=98/2	polymorphism

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: rs753464609; hg19: chr6-41613957;