NM_001370592.1:c.245G>A

Variant names:

• chr17-75267849-C-T
• rs2077556423
• NM_001370592.1:c.245G>A

Variant summary

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

The NM_001370592.1(MIF4GD):​c.245G>A​(p.Arg82Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,612 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MIF4GD NM_001370592.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.44
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.245G>A	p.Arg82Gln	missense	Exon 4 of 6	NP_001357521.1	A0A0S2Z5K9
	MIF4GD	NM_001242498.2		c.368G>A	p.Arg123Gln	missense	Exon 5 of 7	NP_001229427.1	A9UHW6-3
	MIF4GD	NM_001365751.1		c.368G>A	p.Arg123Gln	missense	Exon 5 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.245G>A	p.Arg82Gln	missense	Exon 4 of 6	ENSP00000321625.8	A9UHW6-1
	MIF4GD	ENST00000618645.5	TSL:1	c.245G>A	p.Arg82Gln	missense	Exon 3 of 5	ENSP00000484245.1	A9UHW6-1
	MIF4GD	ENST00000886607.1		c.368G>A	p.Arg123Gln	missense	Exon 5 of 7	ENSP00000556666.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461612 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727104

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5738

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111980

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.033	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.22
Sift	Benign	0.24	T
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.60		Loss of MoRF binding (P = 0.0309)
MVP		0.31
MPC		0.41
ClinPred		0.89	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2077556423; hg19: chr17-73263930;