chr7-114923029-G-C

Variant names:

• chr7-114923029-G-C
• rs1410923033
• NM_001166345.3:c.-5G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199072.5(MDFIC):​c.323G>C​(p.Arg108Pro) 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. 12/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R108Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MDFIC NM_199072.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.283
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1861977).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDFIC	NM_001166345.3	MANE Select	c.-5G>C		5_prime_UTR	Exon 2 of 5	NP_001159817.1	Q9P1T7-2
	MDFIC	NM_199072.5		c.323G>C	p.Arg108Pro	missense	Exon 2 of 5	NP_951038.1	Q9P1T7-1
	MDFIC	NM_001166346.1		c.323G>C	p.Arg108Pro	missense	Exon 2 of 3	NP_001159818.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MDFIC	ENST00000393486.6	TSL:1 MANE Select	c.-5G>C		5_prime_UTR	Exon 2 of 5	ENSP00000377126.1	Q9P1T7-2
	MDFIC	ENST00000423503.1	TSL:1	c.-5G>C		5_prime_UTR	Exon 1 of 2	ENSP00000401623.1	C9J104
	MDFIC	ENST00000963682.1		c.-5G>C		5_prime_UTR	Exon 2 of 6	ENSP00000633741.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	15
DANN	Uncertain	0.99
Eigen	Benign	-0.032
Eigen_PC	Benign	-0.039
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.80	T
PhyloP100		0.28
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.036
Sift	Benign	0.13	T
Sift4G	Benign	0.19	T
Vest4		0.34
MutPred		0.32		Gain of catalytic residue at R108 (P = 0.0075)
MVP		0.24
ClinPred		0.97	D
GERP RS		2.7
PromoterAI		-0.017	Neutral
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

Other links and lift over

dbSNP: rs1410923033; hg19: chr7-114563084;