7-114923034-A-C

Variant names:

• chr7-114923034-A-C
• NM_001166345.3:c.1A>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_199072.5(MDFIC):​c.328A>C​(p.Met110Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MDFIC NM_199072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.57

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MDFIC	NM_001166345.3	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 5	ENST00000393486.6	NP_001159817.1
MDFIC	NM_199072.5	c.328A>C	p.Met110Leu	missense_variant	Exon 2 of 5		NP_951038.1
MDFIC	NM_001166346.1	c.328A>C	p.Met110Leu	missense_variant	Exon 2 of 3		NP_001159818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MDFIC	ENST00000393486.6	c.1A>C	p.Met1?	initiator_codon_variant	Exon 2 of 5	1	NM_001166345.3	ENSP00000377126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1228338 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 602280

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.328A>C (p.M110L) alteration is located in exon 2 (coding exon 2) of the MDFIC gene. This alteration results from a A to C substitution at nucleotide position 328, causing the methionine (M) at amino acid position 110 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.13	.;T;.;T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.50	D
LIST_S2	Benign	0.38	T;D;T;.;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.74	T
PROVEAN	Benign	-0.89	N;N;.;D;D
REVEL	Uncertain	0.31
Sift	Benign	0.23	T;D;.;D;D
Sift4G	Benign	0.097	T;D;T;D;D
Polyphen		0.94	.;P;.;.;.
Vest4		0.42
MutPred		0.99		.;Loss of catalytic residue at M1 (P = 0.2392);.;Loss of catalytic residue at M1 (P = 0.2392);Loss of catalytic residue at M1 (P = 0.2392);
MVP		0.31
ClinPred		0.91	D
GERP RS		4.5
Varity_R		0.86
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-114563089;