Genetic Variant TIMM22:p.Val33Leu (chr17-997239-G-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_013337.4(TIMM22):c.97G>C(p.Val33Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00624 in 1,613,452 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0064 ( 32 hom. )

Consequence

TIMM22
NM_013337.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2B:1

Conservation

PhyloP100: 4.42

Publications

11 publications found

Variant links:

Genes affected

TIMM22 (HGNC:17317): (translocase of inner mitochondrial membrane 22) Multipass transmembrane proteins are brought into mitochondria and inserted into the mitochondrial inner membrane by way of the TIM22 complex. This complex has six subunits and is a twin-pore translocase. The protein encoded by this gene is a subunit of TIM22 and represents the voltage-activated and signal-gated channel. [provided by RefSeq, Jul 2016]

TIMM22 Gene-Disease associations (from GenCC):

mitochondrial disease
Inheritance: AR Classification: MODERATE Submitted by: PanelApp Australia
combined oxidative phosphorylation deficiency 43
Inheritance: Unknown, AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

TIMM22 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008468449).

BP6

Variant 17-997239-G-C is Benign according to our data. Variant chr17-997239-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 869639.

BS2

High Homozygotes in GnomAd4 at 3 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013337.4. 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
	TIMM22	NM_013337.4	MANE Select	c.97G>C	p.Val33Leu	missense	Exon 1 of 4	NP_037469.2	Q9Y584

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM22	ENST00000327158.5	TSL:1 MANE Select	c.97G>C	p.Val33Leu	missense	Exon 1 of 4	ENSP00000320236.2	Q9Y584
	TIMM22	ENST00000857801.1		c.97G>C	p.Val33Leu	missense	Exon 1 of 2	ENSP00000527860.1

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

661

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00130

Gnomad AMI

AF:

0.0307

Gnomad AMR

AF:

0.00399

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000752

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00705

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00423

AC:

1057

AN:

249592

AF XY:

0.00416

show subpopulations

Gnomad AFR exome

AF:

0.00137

Gnomad AMR exome

AF:

0.00379

Gnomad ASJ exome

AF:

0.00790

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000696

Gnomad NFE exome

AF:

0.00672

Gnomad OTH exome

AF:

0.00706

GnomAD4 exome

AF:

0.00644

AC:

9405

AN:

1461088

Hom.:

Cov.:

AF XY:

0.00622

AC XY:

4520

AN XY:

726834

show subpopulations

African (AFR)

AF:

0.00149

AC:

AN:

33478

American (AMR)

AF:

0.00434

AC:

194

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00830

AC:

217

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.000325

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.000910

AC:

AN:

52752

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00758

AC:

8425

AN:

1111920

Other (OTH)

AF:

0.00689

AC:

416

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

586

1173

1759

2346

2932

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<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:

0.00433

AC:

660

AN:

152364

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

274

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00130

AC:

AN:

41596

American (AMR)

AF:

0.00399

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000752

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00706

AC:

480

AN:

68032

Other (OTH)

AF:

0.00473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

104

138

173

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:

0.00521

Hom.:

Bravo

AF:

0.00458

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00837

AC:

ExAC

AF:

0.00402

AC:

487

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00763

EpiControl

AF:

0.00699

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Combined oxidative phosphorylation deficiency 43 (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.061

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Uncertain

0.89

M_CAP

Benign

0.048

MetaRNN

Benign

0.0085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

PhyloP100

4.4

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.3

REVEL

Benign

0.098

Sift

Benign

0.032

Sift4G

Benign

0.13

Polyphen

0.36

Vest4

0.39

MutPred

0.27

Loss of helix (P = 0.0558)

MVP

0.34

MPC

0.18

ClinPred

0.057

GERP RS

5.4

PromoterAI

-0.061

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.66

gMVP

0.71

Mutation Taster

=85/15

disease causing (ClinVar)

(source)

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

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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