chrX-48893927-G-A

Position:

chrX-48893927-G-A

Variant summary

Our verdict is Likely benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -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/exons	MANE	Protein
TIMM17B	NM_001395498.1 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	5/6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2 linkuse as main transcript	c.553C>T	p.Arg185Cys	missense_variant	7/8		NP_001161419.1
TIMM17B	NM_001395497.1 linkuse as main transcript	c.553C>T	p.Arg185Cys	missense_variant	6/7		NP_001382426.1
TIMM17B	NM_005834.5 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	6/7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	5/6		NM_001395498.1	ENSP00000512416	P1	O60830-1

Frequencies

GnomAD3 genomes

AF:

0.0000890

AC:

AN:

112357

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34535

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

GnomAD3 exomes

AF:

0.0000780

AC:

AN:

179549

Hom.:

AF XY:

0.0000620

AC XY:

AN XY:

64541

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.0000379

Gnomad4 AMR exome

AF:

0.0000285

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000332

Gnomad4 SAS exome

AF:

0.0000185

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000414

Gnomad4 OTH exome

AF:

0.0000435

GnomAD4 genome

AF:

0.0000890

AC:

AN:

112409

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34597

show subpopulations

Gnomad4 AFR

AF:

0.0000323

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000150

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.000106

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 05, 2022

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

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;.;.

MutationTaster

Benign

1.0

D;D

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over