NM_001395498.1:c.403C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001395498.1(TIMM17B):c.403C>T(p.Arg135Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000301 in 1,208,614 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 117 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.00032 ( 0 hom. 117 hem. )

Consequence

TIMM17B
NM_001395498.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

0 publications found

Variant links:

Genes affected

TIMM17B (HGNC:17310): (translocase of inner mitochondrial membrane 17B) This gene encodes a multipass transmembrane protein that forms an integral component of the mitochondrial translocase TIM23 complex. This complex facilitates the transport of mitochondrial proteins from the cytosol across the mitochondrial inner membrane and into the mitochondrion. There is a pseudogene for this gene on chromosome 12. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

TIMM17B links:

PQBP1 (HGNC:9330): (polyglutamine binding protein 1) This gene encodes a nuclear polyglutamine-binding protein that is involved with transcription activation. The encoded protein contains a WW domain. Mutations in this gene have been found in patients with Renpenning syndrome 1 and other syndromes with X-linked cognitive disability. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.[provided by RefSeq, Nov 2009]

PQBP1 Gene-Disease associations (from GenCC):

Renpenning syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
hamel cerebro-palato-cardiac syndrome
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Golabi-Ito-hall type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Porteous type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
X-linked intellectual disability, Sutherland-Haan type
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

PQBP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.864

BS2

High Hemizygotes in GnomAdExome4 at 117 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMM17B	NM_001395498.1 link	c.403C>T	p.Arg135Cys	missense_variant	Exon 5 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2 link	c.553C>T	p.Arg185Cys	missense_variant	Exon 7 of 8		NP_001161419.1
TIMM17B	NM_001395497.1 link	c.553C>T	p.Arg185Cys	missense_variant	Exon 6 of 7		NP_001382426.1
TIMM17B	NM_005834.5 link	c.403C>T	p.Arg135Cys	missense_variant	Exon 6 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 link	c.403C>T	p.Arg135Cys	missense_variant	Exon 5 of 6		NM_001395498.1	ENSP00000512416.1		O60830-1

Frequencies

GnomAD3 genomes

AF:

0.0000890

AC:

AN:

112357

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

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:

0.000150

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.0000780

AC:

AN:

179549

AF XY:

0.0000620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000368

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000730

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000323

AC:

354

AN:

1096205

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

117

AN XY:

361641

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26362

American (AMR)

AF:

0.0000285

AC:

AN:

35131

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19358

East Asian (EAS)

AF:

0.0000332

AC:

AN:

30162

South Asian (SAS)

AF:

0.0000185

AC:

AN:

53916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4044

European-Non Finnish (NFE)

AF:

0.000414

AC:

348

AN:

840751

Other (OTH)

AF:

0.0000435

AC:

AN:

46005

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112409

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34597

show subpopulations

African (AFR)

AF:

0.0000323

AC:

AN:

30975

American (AMR)

AF:

0.00

AC:

AN:

10670

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2657

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2738

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6199

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53190

Other (OTH)

AF:

0.000657

AC:

AN:

1522

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000967

Hom.:

Bravo

AF:

0.0000869

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 05, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.553C>T (p.R185C) alteration is located in exon 7 (coding exon 6) of the TIMM17B gene. This alteration results from a C to T substitution at nucleotide position 553, causing the arginine (R) at amino acid position 185 to be replaced by a cysteine (C). 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

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

.;T;.;T

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.93

.;D;D;D

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.86

D;D;D;D

MetaSVM

Benign

-0.50

MutationAssessor

Uncertain

2.6

.;M;.;.

PhyloP100

3.8

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.0

.;D;D;.

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

.;D;.;.

Vest4

0.83

MVP

0.79

MPC

0.60

ClinPred

0.64

GERP RS

4.7

Varity_R

0.81

gMVP

0.97

Mutation Taster

=98/2

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_001395498.1:c.403C>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over