7-114942305-A-C

Position:

• chr7-114942305-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001166345.3(MDFIC):​c.125A>C​(p.Asp42Ala) 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 benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MDFIC NM_001166345.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061288506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDFIC	NM_001166345.3	c.125A>C	p.Asp42Ala	missense_variant	3/5	ENST00000393486.6	NP_001159817.1
MDFIC	NM_199072.5	c.452A>C	p.Asp151Ala	missense_variant	3/5		NP_951038.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDFIC	ENST00000393486.6	c.125A>C	p.Asp42Ala	missense_variant	3/5	1	NM_001166345.3	ENSP00000377126.1
MDFIC	ENST00000427207.5	c.83A>C	p.Asp28Ala	missense_variant	2/4	3		ENSP00000392098.1
MDFIC	ENST00000498196	c.-41A>C		5_prime_UTR_variant	2/4	4		ENSP00000418337.1
MDFIC	ENST00000431629.5	n.95A>C		non_coding_transcript_exon_variant	2/5	5		ENSP00000416668.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.452A>C (p.D151A) alteration is located in exon 3 (coding exon 3) of the MDFIC gene. This alteration results from a A to C substitution at nucleotide position 452, causing the aspartic acid (D) at amino acid position 151 to be replaced by an alanine (A). 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
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Benign	0.12	.;T;.;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.42	T;T;T;T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.061	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	.;L;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N;N;.;D
REVEL	Benign	0.071
Sift	Benign	0.19	T;D;.;D
Sift4G	Benign	0.14	T;D;T;D
Polyphen		0.26	.;B;.;.
Vest4		0.17
MutPred		0.095		.;Gain of helix (P = 0.0696);.;.;
MVP		0.23
ClinPred		0.12	T
GERP RS		1.7
Varity_R		0.061
gMVP		0.17

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

LitVar

Other links and lift over

dbSNP: rs1199925291; hg19: chr7-114582360;