17-75270116-T-A

Position:

• chr17-75270116-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001370592.1(MIF4GD):​c.80A>T​(p.Lys27Ile) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MIF4GD NM_001370592.1 missense, splice_region
• Scores: Splicing: ADA: 0.8793
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

Genes affected

MIF4GD (HGNC:24030): (MIF4G domain containing) This gene encodes a protein which interacts with the N-terminus of the stem-loop binding protein (SLBP) and the 3' end of histone mRNA. This interaction facilitates the activation of histone mRNA translation. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

MIF4GD (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.767

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MIF4GD	NM_001370592.1	c.80A>T	p.Lys27Ile	missense_variant, splice_region_variant	2/6	ENST00000325102.13	NP_001357521.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MIF4GD	ENST00000325102.13	c.80A>T	p.Lys27Ile	missense_variant, splice_region_variant	2/6	2	NM_001370592.1	ENSP00000321625.8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 03, 2023

The c.80A>T (p.K27I) alteration is located in exon 2 (coding exon 1) of the MIF4GD gene. This alteration results from a A to T substitution at nucleotide position 80, causing the lysine (K) at amino acid position 27 to be replaced by an isoleucine (I). 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	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	34
DANN	Benign	0.97
DEOGEN2	Benign	0.055	T;T;.;.;.;.;.;.;.;T;.;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	.;D;T;.;T;D;T;D;T;D;T;T;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.5	M;M;M;M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.94	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N;.;N;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.37
Sift	Benign	0.38	T;.;D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;.;D;D;.;.;.;D
Polyphen		0.98	D;D;D;.;.;.;.;.;.;.;.;.;.
Vest4		0.70
MutPred		0.69		Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);Loss of solvent accessibility (P = 0.0083);
MVP		0.49
MPC		1.1
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.42
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.88
dbscSNV1_RF	Benign	0.52
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: chr17-73266197;