8-17027538-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181723.3(MICU3):c.259G>C(p.Gly87Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000307 in 1,280,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: MICU3 NM_181723.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20277694).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICU3	NM_181723.3	c.259G>C	p.Gly87Arg	missense_variant	1/15	ENST00000318063.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICU3	ENST00000318063.10	c.259G>C	p.Gly87Arg	missense_variant	1/15	1	NM_181723.3	P1
MICU3	ENST00000522235.5			upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152034 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00143

GnomAD4 exome AF: 0.000319 AC: 360 AN: 1128186 Hom.: 0 Cov.: 34 AF XY: 0.000313 AC XY: 169 AN XY: 540090

Gnomad4 AFR exome AF: 0.0000431

Gnomad4 AMR exome AF: 0.000349

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00108

Gnomad4 FIN exome AF: 0.000204

Gnomad4 NFE exome AF: 0.000316

Gnomad4 OTH exome AF: 0.000285

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152146 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74364

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000196

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00142

Bravo AF: 0.000230

ExAC AF: 0.000137 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2022

The c.259G>C (p.G87R) alteration is located in exon 1 (coding exon 1) of the MICU3 gene. This alteration results from a G to C substitution at nucleotide position 259, causing the glycine (G) at amino acid position 87 to be replaced by an arginine (R). 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	Benign	0.17
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Benign	-0.29
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.061
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.88	N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.22	N
REVEL	Benign	0.073
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.25	T
Polyphen		0.99	D
Vest4		0.49
MutPred		0.27		Loss of sheet (P = 0.0357);
MVP		0.37
MPC		1.4
ClinPred		0.76	D
GERP RS		3.4
Varity_R		0.14
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs535636469; hg19: chr8-16885047;