10-72368347-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001195518.2(MICU1):c.1279G>A(p.Glu427Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000036 (0 hom.)
• Consequence: MICU1 NM_001195518.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.88

Genes affected

MICU1 (HGNC:1530): (mitochondrial calcium uptake 1) This gene encodes an essential regulator of mitochondrial Ca2+ uptake under basal conditions. The encoded protein interacts with the mitochondrial calcium uniporter, a mitochondrial inner membrane Ca2+ channel, and is essential in preventing mitochondrial Ca2+ overload, which can cause excessive production of reactive oxygen species and cell stress. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Mar 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity MICU1_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MICU1	NM_001195518.2	c.1279G>A	p.Glu427Lys	missense_variant	12/12	ENST00000361114.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MICU1	ENST00000361114.10	c.1279G>A	p.Glu427Lys	missense_variant	12/12	1	NM_001195518.2	P4

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000282 AC: 7 AN: 248666 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 134964

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461162 Hom.: 0 Cov.: 31 AF XY: 0.0000344 AC XY: 25 AN XY: 726748

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000396

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152152 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74330

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000962 Hom.: 0

Bravo AF: 0.0000416

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 31, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 429 of the MICU1 protein (p.Glu429Lys). This variant is present in population databases (rs776805865, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with MICU1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1216544). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MICU1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2023	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.17
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Benign	-0.023
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Uncertain	0.43	T;T;T;T;T;T
MetaSVM	Benign	-0.75	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.63	N;N;.;.;N;N
REVEL	Uncertain	0.36
Sift	Benign	0.44	T;T;.;.;T;T
Sift4G	Benign	0.48	T;T;.;T;T;T
Polyphen		0.41, 0.12	.;B;.;.;B;B
Vest4		0.77
MVP		0.36
MPC		0.32
ClinPred		0.13	T
GERP RS		5.9
Varity_R		0.38
gMVP		0.84

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: rs776805865; hg19: chr10-74128105;