Genetic Variant MDFIC:c.-45C>T (chr7-114922989-C-T) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_199072.5(MDFIC):c.283C>T(p.Arg95*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000291 in 1,376,298 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

MDFIC
NM_199072.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0740

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_199072.5. 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>T		5_prime_UTR	Exon 2 of 5	NP_001159817.1	Q9P1T7-2
MDFIC	NM_199072.5		c.283C>T	p.Arg95*	stop_gained	Exon 2 of 5	NP_951038.1	Q9P1T7-1
MDFIC	NM_001166346.1		c.283C>T	p.Arg95*	stop_gained	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>T	5_prime_UTR	Exon 2 of 5	ENSP00000377126.1	Q9P1T7-2
MDFIC	ENST00000423503.1	TSL:1	c.-45C>T	5_prime_UTR	Exon 1 of 2	ENSP00000401623.1	C9J104
MDFIC	ENST00000963682.1		c.-45C>T	5_prime_UTR	Exon 2 of 6	ENSP00000633741.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000291

AC:

AN:

1376298

Hom.:

Cov.:

AF XY:

0.00000293

AC XY:

AN XY:

683606

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000354

AC:

AN:

28264

American (AMR)

AF:

0.00

AC:

AN:

35384

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23628

East Asian (EAS)

AF:

0.00

AC:

AN:

31368

South Asian (SAS)

AF:

0.00

AC:

AN:

77882

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48968

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4674

European-Non Finnish (NFE)

AF:

0.00000280

AC:

AN:

1070430

Other (OTH)

AF:

0.00

AC:

AN:

55700

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.238

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.036

FATHMM_MKL

Benign

0.048

PhyloP100

-0.074

Vest4

0.073

GERP RS

1.6

PromoterAI

-0.047

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over