Genetic Variant NM_001166345.3:c.-198G>T (chr7-114922546-G-T) – 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.-198G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000189 in 1,266,490 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00091 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

MDFIC
NM_001166345.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.410

Publications

1 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=0.0046138167).

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.-198G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	NP_001159817.1	Q9P1T7-2
MDFIC	NM_001166345.3	MANE Select	c.-198G>T		5_prime_UTR	Exon 1 of 5	NP_001159817.1	Q9P1T7-2
MDFIC	NM_199072.5		c.130G>T	p.Gly44Cys	missense	Exon 1 of 5	NP_951038.1	Q9P1T7-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MDFIC	ENST00000393486.6	TSL:1 MANE Select	c.-198G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000377126.1	Q9P1T7-2
MDFIC	ENST00000393486.6	TSL:1 MANE Select	c.-198G>T	5_prime_UTR	Exon 1 of 5	ENSP00000377126.1	Q9P1T7-2
MDFIC	ENST00000963682.1		c.-198G>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 6	ENSP00000633741.1

Frequencies

GnomAD3 genomes

AF:

0.000880

AC:

134

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000110

AC:

AN:

27330

AF XY:

0.000144

show subpopulations

Gnomad AFR exome

AF:

0.00174

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000898

AC:

100

AN:

1114182

Hom.:

Cov.:

AF XY:

0.0000851

AC XY:

AN XY:

528784

show subpopulations

African (AFR)

AF:

0.00320

AC:

AN:

23778

American (AMR)

AF:

0.000216

AC:

AN:

9276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14616

East Asian (EAS)

AF:

0.00

AC:

AN:

27794

South Asian (SAS)

AF:

0.00

AC:

AN:

22502

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3450

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

931564

Other (OTH)

AF:

0.000247

AC:

AN:

44598

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

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:

0.000913

AC:

139

AN:

152308

Hom.:

Cov.:

AF XY:

0.00111

AC XY:

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00310

AC:

129

AN:

41590

American (AMR)

AF:

0.000326

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5134

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000641

Hom.:

Bravo

AF:

0.000948

ESP6500AA

AF:

0.000903

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000147

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

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

0.28

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.64

CADD

Benign

8.3

(source)

DANN

Benign

0.96

Eigen

Benign

-0.87

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0036

LIST_S2

Benign

0.31

MetaRNN

Benign

0.0046

MetaSVM

Benign

-0.99

PhyloP100

-0.41

PROVEAN

Benign

0.040

REVEL

Benign

0.0070

Sift

Uncertain

0.014

Sift4G

Uncertain

0.016

Vest4

0.15

MVP

0.076

ClinPred

0.043

GERP RS

-2.3

PromoterAI

0.015

Neutral

(source)

gMVP

0.13

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