8-17027656-A-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.377A>C(p.Glu126Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000262 in 1,146,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. E126D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: MICU3 NM_181723.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.80

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=0.20016733).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICU3	NM_181723.3	c.377A>C	p.Glu126Ala	missense_variant	1/15	ENST00000318063.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICU3	ENST00000318063.10	c.377A>C	p.Glu126Ala	missense_variant	1/15	1	NM_181723.3	P1
MICU3	ENST00000522235.5	n.79A>C		non_coding_transcript_exon_variant	1/3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000262 AC: 3 AN: 1146720 Hom.: 0 Cov.: 34 AF XY: 0.00000363 AC XY: 2 AN XY: 551170

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: 0.0000806

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Mar 29, 2022

The c.377A>C (p.E126A) alteration is located in exon 1 (coding exon 1) of the MICU3 gene. This alteration results from a A to C substitution at nucleotide position 377, causing the glutamic acid (E) at amino acid position 126 to be replaced by an alanine (A). 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	0.24
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.055
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	0.79	D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.13
Sift	Benign	0.049	D
Sift4G	Benign	0.13	T
Polyphen		0.95	P
Vest4		0.38
MutPred		0.38		Loss of solvent accessibility (P = 0.0224);
MVP		0.36
MPC		0.94
ClinPred		0.87	D
GERP RS		3.2
Varity_R		0.18
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-16885165;