8-17027286-G-C

Variant names:

• chr8-17027286-G-C
• rs781466293
• NM_181723.3:c.7G>C

Variant summary

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

The NM_181723.3(MICU3):​c.7G>C​(p.Ala3Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000751 in 1,331,726 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. A3T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.5e-7 (0 hom.)
• Consequence: MICU3 NM_181723.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.67
• Publications: 0 publications found

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]

ENSG00000289225 (HGNC:):

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, 0.792

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICU3	NM_181723.3	MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 15	NP_859074.1	Q86XE3
	MICU3	NM_001349810.2		c.7G>C	p.Ala3Pro	missense	Exon 1 of 15	NP_001336739.1
	MICU3	NM_001413217.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 14	NP_001400146.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MICU3	ENST00000318063.10	TSL:1 MANE Select	c.7G>C	p.Ala3Pro	missense	Exon 1 of 15	ENSP00000321455.5	Q86XE3
	MICU3	ENST00000952687.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 15	ENSP00000622746.1
	MICU3	ENST00000952690.1		c.7G>C	p.Ala3Pro	missense	Exon 1 of 15	ENSP00000622749.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.51e-7 AC: 1 AN: 1331726 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 660802

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 27252

American (AMR) AF: 0.00 AC: 0 AN: 32208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21364

East Asian (EAS) AF: 0.00 AC: 0 AN: 29388

South Asian (SAS) AF: 0.00 AC: 0 AN: 74520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4856

European-Non Finnish (NFE) AF: 9.50e-7 AC: 1 AN: 1053142

Other (OTH) AF: 0.00 AC: 0 AN: 54004

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.0087	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.015	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.7
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.83	N
REVEL	Benign	0.20
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.37		Loss of helix (P = 0.0041)
MVP		0.59
MPC		1.1
ClinPred		0.71	D
GERP RS		3.5
PromoterAI		-0.32	Neutral
Varity_R		0.52
gMVP		0.69
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs781466293; hg19: chr8-16884795;