7-114922570-T-C

Position:

• chr7-114922570-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_199072.5(MDFIC):​c.154T>C​(p.Phe52Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,116,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: MDFIC NM_199072.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11499119).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDFIC	NM_001166345.3	c.-174T>C		5_prime_UTR_variant	1/5	ENST00000393486.6	NP_001159817.1
MDFIC	NM_199072.5	c.154T>C	p.Phe52Leu	missense_variant	1/5		NP_951038.1
MDFIC	NM_001166346.1	c.154T>C	p.Phe52Leu	missense_variant	1/3		NP_001159818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDFIC	ENST00000393486	c.-174T>C		5_prime_UTR_variant	1/5	1	NM_001166345.3	ENSP00000377126.1
MDFIC	ENST00000448022.1	c.-174T>C		5_prime_UTR_variant	1/3	2		ENSP00000412153.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1116736 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 530106

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: 0.0000447

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000969 AC: 1

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

Aug 29, 2023

The c.154T>C (p.F52L) alteration is located in exon 1 (coding exon 1) of the MDFIC gene. This alteration results from a T to C substitution at nucleotide position 154, causing the phenylalanine (F) at amino acid position 52 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	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	17
DANN	Benign	0.97
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.26	T;T
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.99	T
PROVEAN	Benign	-0.32	N;.
REVEL	Benign	0.048
Sift	Benign	0.065	T;.
Sift4G	Benign	0.46	T;T
Vest4		0.30
MutPred		0.16		Loss of methylation at K56 (P = 0.0746);Loss of methylation at K56 (P = 0.0746);
MVP		0.040
ClinPred		0.70	D
GERP RS		2.2
gMVP		0.085

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: rs764512112; hg19: chr7-114562625;