Genetic Variant NM_181723.3:c.378G>C (chr8-17027657-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_181723.3(MICU3):c.378G>C(p.Glu126Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000102 in 1,299,292 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E126A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 1 hom. )

Consequence

MICU3
NM_181723.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.39

Publications

0 publications found

Variant links:

Genes affected

MICU3 (HGNC:27820): (mitochondrial calcium uptake family member 3) Predicted to enable calcium ion binding activity. Predicted to be involved in calcium import into the mitochondrion and mitochondrial calcium ion homeostasis. Predicted to be located in mitochondrial inner membrane. Predicted to be part of uniplex complex. [provided by Alliance of Genome Resources, Apr 2022]

MICU3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.051063657).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181723.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MICU3	NM_181723.3	MANE Select	c.378G>C	p.Glu126Asp	missense	Exon 1 of 15	NP_859074.1	Q86XE3
MICU3	NM_001349810.2		c.378G>C	p.Glu126Asp	missense	Exon 1 of 15	NP_001336739.1
MICU3	NM_001413217.1		c.378G>C	p.Glu126Asp	missense	Exon 1 of 14	NP_001400146.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MICU3	ENST00000318063.10	TSL:1 MANE Select	c.378G>C	p.Glu126Asp	missense	Exon 1 of 15	ENSP00000321455.5	Q86XE3
MICU3	ENST00000952687.1		c.378G>C	p.Glu126Asp	missense	Exon 1 of 15	ENSP00000622746.1
MICU3	ENST00000952690.1		c.378G>C	p.Glu126Asp	missense	Exon 1 of 15	ENSP00000622749.1

Frequencies

GnomAD3 genomes

AF:

0.000591

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00

AC:

AN:

3066

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000366

AC:

AN:

1146964

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

551260

show subpopulations

African (AFR)

AF:

0.00141

AC:

AN:

23350

American (AMR)

AF:

0.00

AC:

AN:

9226

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15650

East Asian (EAS)

AF:

0.00

AC:

AN:

26948

South Asian (SAS)

AF:

0.00

AC:

AN:

37214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25744

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3124

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

959286

Other (OTH)

AF:

0.000194

AC:

AN:

46422

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000591

AC:

AN:

152328

Hom.:

Cov.:

AF XY:

0.000456

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

41596

American (AMR)

AF:

0.000196

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.000207

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68026

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000285

Hom.:

Bravo

AF:

0.000514

ExAC

AF:

0.0000682

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.014

Eigen

Benign

-0.39

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.56

M_CAP

Benign

0.029

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

1.4

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.61

REVEL

Benign

0.062

Sift

Benign

0.075

Sift4G

Benign

0.075

Polyphen

0.012

Vest4

0.28

MutPred

0.33

Loss of loop (P = 0.1242)

MVP

0.17

MPC

0.83

ClinPred

0.61

GERP RS

2.3

PromoterAI

0.16

Neutral

(source)

Varity_R

0.084

gMVP

0.20

Mutation Taster

=93/7

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over