Genetic Variant NM_001195518.2:c.735+1G>A (chr10-72477173-C-T) – ACMG Classification: Pathogenic (22 pts)

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1PS3PM2PP5_Very_Strong

The NM_001195518.2(MICU1):c.735+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,540,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001653101: "In vitro functional studies using patient mRNA have shown that this variant affects splicing and leads to markedly decreased MICU1 mRNA and loss of protein levels." PMID:24336167" and additional evidence is available in ClinVar.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MICU1
NM_001195518.2 splice_donor, intron

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 7.88

Publications

5 publications found

Variant links:

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]

MICU1 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
proximal myopathy with extrapyramidal signs
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet

MICU1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 22 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PS3

PS3 evidence extracted from ClinVar submissions: SCV001653101: "In vitro functional studies using patient mRNA have shown that this variant affects splicing and leads to markedly decreased MICU1 mRNA and loss of protein levels." PMID: 24336167; SCV003441630: Studies have shown that disruption of this splice site results in retention of 155 bp of intron 8 and introduces a premature termination codon (PMID: 24336167).

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 10-72477173-C-T is Pathogenic according to our data. Variant chr10-72477173-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 101046.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001195518.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MICU1	NM_001195518.2	MANE Select	c.735+1G>A	splice_donor intron	N/A	NP_001182447.1	Q9BPX6-1
MICU1	NM_001441218.1		c.966+1G>A	splice_donor intron	N/A	NP_001428147.1
MICU1	NM_001441219.1		c.903+1G>A	splice_donor intron	N/A	NP_001428148.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MICU1	ENST00000361114.10	TSL:1 MANE Select	c.735+1G>A		splice_donor intron	N/A	ENSP00000354415.5	Q9BPX6-1
MICU1	ENST00000603011.5	TSL:5	c.634G>A	p.Ala212Thr	missense	Exon 7 of 7	ENSP00000474192.1	S4R3D7
MICU1	ENST00000964210.1		c.966+1G>A		splice_donor intron	N/A	ENSP00000634269.1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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

GnomAD2 exomes

AF:

0.0000548

AC:

AN:

146006

AF XY:

0.0000260

show subpopulations

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:

0.000139

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000187

AC:

AN:

1388194

Hom.:

Cov.:

AF XY:

0.0000131

AC XY:

AN XY:

684600

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30992

American (AMR)

AF:

0.00

AC:

AN:

33442

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24862

East Asian (EAS)

AF:

0.00

AC:

AN:

35752

South Asian (SAS)

AF:

0.00

AC:

AN:

76820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49190

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4876

European-Non Finnish (NFE)

AF:

0.0000233

AC:

AN:

1074726

Other (OTH)

AF:

0.0000174

AC:

AN:

57534

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152138

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

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:

0.0000847

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000140

AC:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Proximal myopathy with extrapyramidal signs (5)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.1

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.56

PhyloP100

7.9

ClinPred

0.76

GERP RS

5.7

Mutation Taster

=11/89

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: 1

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