Genetic Variant NM_001166345.3:c.-45C>G (chr7-114922989-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001166345.3(MDFIC):c.-45C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000076 in 1,527,292 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

MDFIC
NM_001166345.3 5_prime_UTR

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.0740

Publications

2 publications found

Variant links:

Genes affected

MDFIC (HGNC:28870): (MyoD family inhibitor domain containing) This gene product is a member of a family of proteins characterized by a specific cysteine-rich C-terminal domain, which is involved in transcriptional regulation of viral genome expression. Alternative translation initiation from an upstream non-AUG (GUG), and an in-frame, downstream AUG codon, results in the production of two isoforms, p40 and p32, respectively, which have different subcellular localization; p32 is mainly found in the cytoplasm, whereas p40 is targeted to the nucleolus. Both isoforms have transcriptional regulatory activity that is attributable to the cysteine-rich C-terminal domain. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

MDFIC Gene-Disease associations (from GenCC):

lymphatic malformation 12
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

MDFIC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013249993).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001166345.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDFIC	NM_001166345.3	MANE Select	c.-45C>G		5_prime_UTR	Exon 2 of 5	NP_001159817.1	Q9P1T7-2
MDFIC	NM_199072.5		c.283C>G	p.Arg95Gly	missense	Exon 2 of 5	NP_951038.1	Q9P1T7-1
MDFIC	NM_001166346.1		c.283C>G	p.Arg95Gly	missense	Exon 2 of 3	NP_001159818.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MDFIC	ENST00000393486.6	TSL:1 MANE Select	c.-45C>G	5_prime_UTR	Exon 2 of 5	ENSP00000377126.1	Q9P1T7-2
MDFIC	ENST00000423503.1	TSL:1	c.-45C>G	5_prime_UTR	Exon 1 of 2	ENSP00000401623.1	C9J104
MDFIC	ENST00000963682.1		c.-45C>G	5_prime_UTR	Exon 2 of 6	ENSP00000633741.1

Frequencies

GnomAD3 genomes

AF:

0.0000530

AC:

AN:

150880

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000171

AC:

AN:

164092

AF XY:

0.000162

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000425

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000785

AC:

108

AN:

1376302

Hom.:

Cov.:

AF XY:

0.0000936

AC XY:

AN XY:

683608

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28264

American (AMR)

AF:

0.00

AC:

AN:

35384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23628

East Asian (EAS)

AF:

0.000606

AC:

AN:

31368

South Asian (SAS)

AF:

0.000758

AC:

AN:

77880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48968

Middle Eastern (MID)

AF:

0.000642

AC:

AN:

4674

European-Non Finnish (NFE)

AF:

0.0000177

AC:

AN:

1070436

Other (OTH)

AF:

0.000144

AC:

AN:

55700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000530

AC:

AN:

150990

Hom.:

Cov.:

AF XY:

0.0000813

AC XY:

AN XY:

73776

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41392

American (AMR)

AF:

0.00

AC:

AN:

15152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3456

East Asian (EAS)

AF:

0.000582

AC:

AN:

5154

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10056

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67652

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000937

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.000166

AC:

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.34

MetaRNN

Benign

0.013

MetaSVM

Benign

-0.80

PhyloP100

-0.074

PROVEAN

Benign

-0.20

REVEL

Benign

0.051

Sift

Uncertain

0.016

Sift4G

Benign

0.11

Vest4

0.27

MutPred

0.20

Gain of loop (P = 0.0051)

MVP

0.22

ClinPred

0.095

GERP RS

1.6

PromoterAI

-0.016

Neutral

(source)

gMVP

0.095

Mutation Taster

=289/11

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over