6-41649742-G-A

Variant names:

• chr6-41649742-G-A
• rs151247971
• NM_005586.4:c.383G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005586.4(MDFI):​c.383G>A​(p.Arg128Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00154 in 1,614,110 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0083 (19 hom., cov: 33)
  • Exomes 𝑓: 0.00083 (13 hom.)
• Consequence: MDFI NM_005586.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.50
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068026483).
• BP6: Variant 6-41649742-G-A is Benign according to our data. Variant chr6-41649742-G-A is described in ClinVar as Benign. ClinVar VariationId is 789591.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00834 (1270/152318) while in subpopulation AFR AF = 0.0281 (1169/41568). AF 95% confidence interval is 0.0268. There are 19 homozygotes in GnomAd4. There are 601 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

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.383G>A	p.Arg128Gln	missense	Exon 4 of 5	NP_005577.1	Q99750
	MDFI	NM_001300804.2		c.383G>A	p.Arg128Gln	missense	Exon 5 of 6	NP_001287733.1	Q99750
	MDFI	NM_001300806.2		c.383G>A	p.Arg128Gln	missense	Exon 3 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.383G>A	p.Arg128Gln	missense	Exon 4 of 5	ENSP00000230321.6	Q99750
	MDFI	ENST00000373051.6	TSL:5	c.383G>A	p.Arg128Gln	missense	Exon 4 of 5	ENSP00000362142.2	Q99750
	MDFI	ENST00000909785.1		c.383G>A	p.Arg128Gln	missense	Exon 4 of 5	ENSP00000579844.1

Frequencies

GnomAD3 genomes AF: 0.00831 AC: 1265 AN: 152200 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

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: 0.000103

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00200 AC: 497 AN: 248742 AF XY: 0.00145

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000540

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000834 AC: 1219 AN: 1461792 Hom.: 13 Cov.: 32 AF XY: 0.000726 AC XY: 528 AN XY: 727198

African (AFR) AF: 0.0276 AC: 924 AN: 33480

American (AMR) AF: 0.00246 AC: 110 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0000594 AC: 66 AN: 1111996

Other (OTH) AF: 0.00176 AC: 106 AN: 60392

GnomAD4 genome AF: 0.00834 AC: 1270 AN: 152318 Hom.: 19 Cov.: 33 AF XY: 0.00807 AC XY: 601 AN XY: 74498

African (AFR) AF: 0.0281 AC: 1169 AN: 41568

American (AMR) AF: 0.00470 AC: 72 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68018

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00285 Hom.: 14

Bravo AF: 0.00931

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00230 AC: 279

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0066	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.5
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.14
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.16
MVP		0.68
MPC		0.27
ClinPred		0.024	T
GERP RS		5.6
Varity_R		0.23
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs151247971; hg19: chr6-41617480; COSMIC: COSV107216482; COSMIC: COSV107216482;