3-122359900-C-A

Variant names:

• chr3-122359900-C-A
• rs1401262247
• NM_001017928.4:c.404G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001017928.4(MIX23):​c.404G>T​(p.Arg135Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000147 in 1,361,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 31)
  • Exomes 𝑓: 0.0000015 (0 hom.)
• Consequence: MIX23 NM_001017928.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.64
• Publications: 0 publications found

Genes affected

MIX23 (HGNC:31136): (mitochondrial matrix import factor 23) Predicted to be located in mitochondrial intermembrane space. Predicted to be active in mitochondrion. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001017928.4. 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
	MIX23	NM_001017928.4	MANE Select	c.404G>T	p.Arg135Leu	missense	Exon 5 of 5	NP_001017928.1	Q4VC31
	MIX23	NM_001308326.2		c.362G>T	p.Arg121Leu	missense	Exon 5 of 5	NP_001295255.1	C9JQ41

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MIX23	ENST00000291458.9	TSL:1 MANE Select	c.404G>T	p.Arg135Leu	missense	Exon 5 of 5	ENSP00000291458.5	Q4VC31
	MIX23	ENST00000906686.1		c.482G>T	p.Arg161Leu	missense	Exon 6 of 6	ENSP00000576745.1
	MIX23	ENST00000479414.1	TSL:3	c.392G>T	p.Arg131Leu	missense	Exon 5 of 5	ENSP00000418810.1	H7C525

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000147 AC: 2 AN: 1361990 Hom.: 0 Cov.: 35 AF XY: 0.00000295 AC XY: 2 AN XY: 678090

African (AFR) AF: 0.00 AC: 0 AN: 27856

American (AMR) AF: 0.00 AC: 0 AN: 34622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23844

East Asian (EAS) AF: 0.00 AC: 0 AN: 31550

South Asian (SAS) AF: 0.00 AC: 0 AN: 77874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5352

European-Non Finnish (NFE) AF: 0.00000189 AC: 2 AN: 1056456

Other (OTH) AF: 0.00 AC: 0 AN: 55044

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		5.6
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.043	D
Polyphen		0.72	P
Vest4		0.75
MutPred		0.68		Loss of MoRF binding (P = 7e-04)
MVP		0.54
MPC		0.73
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.59
gMVP		0.93
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.27		Position offset: 19

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1401262247; hg19: chr3-122078747;