Genetic Variant MIX23:p.Arg133His (chr3-122359906-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001017928.4(MIX23):c.398G>A(p.Arg133His) variant causes a missense change. The variant allele was found at a frequency of 0.0000401 in 1,569,856 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000068 ( 1 hom., cov: 31)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

MIX23
NM_001017928.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06

Variant links:

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]

MIX23 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MIX23	NM_001017928.4 link	c.398G>A	p.Arg133His	missense_variant	Exon 5 of 5	ENST00000291458.9	NP_001017928.1	Q4VC31
MIX23	NM_001308326.2 link	c.356G>A	p.Arg119His	missense_variant	Exon 5 of 5		NP_001295255.1	Q4VC31C9JQ41
MIX23	XM_047447427.1 link	c.368G>A	p.Arg123His	missense_variant	Exon 6 of 6		XP_047303383.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MIX23	ENST00000291458.9 link	c.398G>A	p.Arg133His	missense_variant	Exon 5 of 5	1	NM_001017928.4	ENSP00000291458.5		Q4VC31

Frequencies

GnomAD3 genomes

AF:

0.0000677

AC:

AN:

147736

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000251

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000642

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000892

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

221646

Hom.:

AF XY:

0.0000495

AC XY:

AN XY:

121200

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000316

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000373

AC:

AN:

1422120

Hom.:

Cov.:

AF XY:

0.0000467

AC XY:

AN XY:

707366

show subpopulations

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:

0.000377

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000201

Gnomad4 OTH exome

AF:

0.0000171

GnomAD4 genome

AF:

0.0000677

AC:

AN:

147736

Hom.:

Cov.:

AF XY:

0.0000697

AC XY:

AN XY:

71742

show subpopulations

Gnomad4 AFR

AF:

0.0000251

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000642

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000892

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.398G>A (p.R133H) alteration is located in exon 5 (coding exon 5) of the CCDC58 gene. This alteration results from a G to A substitution at nucleotide position 398, causing the arginine (R) at amino acid position 133 to be replaced by a histidine (H). 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

0.96

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.32

T;.;T

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Benign

0.018

MetaRNN

Uncertain

0.43

T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.5

M;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.054

T;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.51

MVP

0.59

MPC

1.6

ClinPred

0.86

GERP RS

4.7

Varity_R

0.33

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over