17-75267575-C-A

Variant names:

• chr17-75267575-C-A
• rs567167777
• NM_001370592.1:c.404G>T

Variant summary

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

The NM_001370592.1(MIF4GD):​c.404G>T​(p.Arg135Leu) 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. 16/22 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. R135Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MIF4GD NM_001370592.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

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]

MRPS7 (HGNC:14499): (mitochondrial ribosomal protein S7) Mammalian mitochondrial ribosomal proteins are encoded by nuclear genes and help in protein synthesis within the mitochondrion. Mitochondrial ribosomes (mitoribosomes) consist of a small 28S subunit and a large 39S subunit. They have an estimated 75% protein to rRNA composition compared to prokaryotic ribosomes, where this ratio is reversed. Another difference between mammalian mitoribosomes and prokaryotic ribosomes is that the latter contain a 5S rRNA. Among different species, the proteins comprising the mitoribosome differ greatly in sequence, and sometimes in biochemical properties, which prevents easy recognition by sequence homology. This gene encodes a 28S subunit protein. In the prokaryotic ribosome, the comparable protein is thought to play an essential role in organizing the 3' domain of the 16 S rRNA in the vicinity of the P- and A-sites. Pseudogenes corresponding to this gene are found on chromosomes 8p and 12p. [provided by RefSeq, Jul 2008]

MRPS7 Gene-Disease associations (from GenCC):

• syndromic sensorineural deafness due to combined oxidative phosphorylation defect

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• combined oxidative phosphorylation deficiency 34

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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=0.19051567).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001370592.1. 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
	MIF4GD	NM_001370592.1	MANE Select	c.404G>T	p.Arg135Leu	missense	Exon 5 of 6	NP_001357521.1	A0A0S2Z5K9
	MIF4GD	NM_001242498.2		c.527G>T	p.Arg176Leu	missense	Exon 6 of 7	NP_001229427.1	A9UHW6-3
	MIF4GD	NM_001365751.1		c.527G>T	p.Arg176Leu	missense	Exon 6 of 7	NP_001352680.1	A9UHW6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIF4GD	ENST00000325102.13	TSL:2 MANE Select	c.404G>T	p.Arg135Leu	missense	Exon 5 of 6	ENSP00000321625.8	A9UHW6-1
	MIF4GD	ENST00000618645.5	TSL:1	c.404G>T	p.Arg135Leu	missense	Exon 4 of 5	ENSP00000484245.1	A9UHW6-1
	MIF4GD	ENST00000886607.1		c.527G>T	p.Arg176Leu	missense	Exon 6 of 7	ENSP00000556666.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.055	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		2.6
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.10
Sift	Benign	0.41	T
Sift4G	Benign	0.10	T
Polyphen		0.25	B
Vest4		0.79
MutPred		0.40		Loss of catalytic residue at R135 (P = 0.1174)
MVP		0.31
MPC		0.31
ClinPred		0.34	T
GERP RS		2.8
Varity_R		0.063
gMVP		0.63

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: rs567167777; hg19: chr17-73263656;