NM_001166345.3:c.125A>C

Variant names:

• chr7-114942305-A-C
• rs1199925291
• NM_001166345.3:c.125A>C

Variant summary

Our verdict is Likely benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D42G) has been classified 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
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDFIC	NM_001166345.3	MANE Select	c.125A>C	p.Asp42Ala	missense	Exon 3 of 5	NP_001159817.1	Q9P1T7-2
	MDFIC	NM_199072.5		c.452A>C	p.Asp151Ala	missense	Exon 3 of 5	NP_951038.1	Q9P1T7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDFIC	ENST00000393486.6	TSL:1 MANE Select	c.125A>C	p.Asp42Ala	missense	Exon 3 of 5	ENSP00000377126.1	Q9P1T7-2
	MDFIC	ENST00000963682.1		c.125A>C	p.Asp42Ala	missense	Exon 3 of 6	ENSP00000633741.1
	MDFIC	ENST00000904588.1		c.125A>C	p.Asp42Ala	missense	Exon 3 of 5	ENSP00000574647.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.071
Sift	Benign	0.19	T
Sift4G	Benign	0.14	T
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
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs1199925291; hg19: chr7-114582360;