7-114923035-T-A

Position:

• chr7-114923035-T-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001166345.3(MDFIC):​c.2T>A​(p.Met1?) variant causes a start lost 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: 8.2e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MDFIC NM_001166345.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.07

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MDFIC	NM_001166345.3	c.2T>A	p.Met1?	start_lost	2/5	ENST00000393486.6	NP_001159817.1
MDFIC	NM_199072.5	c.329T>A	p.Met110Lys	missense_variant	2/5		NP_951038.1
MDFIC	NM_001166346.1	c.329T>A	p.Met110Lys	missense_variant	2/3		NP_001159818.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MDFIC	ENST00000393486.6	c.2T>A	p.Met1?	start_lost	2/5	1	NM_001166345.3	ENSP00000377126.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.17e-7 AC: 1 AN: 1224662 Hom.: 0 Cov.: 32 AF XY: 0.00000167 AC XY: 1 AN XY: 600394

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: 0.00000100

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.329T>A (p.M110K) alteration is located in exon 2 (coding exon 2) of the MDFIC gene. This alteration results from a T to A substitution at nucleotide position 329, causing the methionine (M) at amino acid position 110 to be replaced by a lysine (K). 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	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;.;T;T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.37	T;D;T;.;D
M_CAP	Pathogenic	0.41	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Benign	-0.55	T
PROVEAN	Benign	-1.9	N;N;.;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D;.;D;D
Sift4G	Benign	0.11	T;D;T;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.72
MutPred		0.99		.;Gain of ubiquitination at M1 (P = 0.0077);.;Gain of ubiquitination at M1 (P = 0.0077);Gain of ubiquitination at M1 (P = 0.0077);
MVP		0.41
ClinPred		0.95	D
GERP RS		4.5
Varity_R		0.93
gMVP		0.40

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: chr7-114563090;