X-48893757-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001395498.1(TIMM17B):c.491G>A(p.Gly164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000344 in 1,162,605 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000035 ( 0 hom. 7 hem. )

Consequence

TIMM17B
NM_001395498.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.757

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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.032497227).

BS2

High Hemizygotes in GnomAdExome4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMM17B	NM_001395498.1 link	c.491G>A	p.Gly164Asp	missense_variant	Exon 6 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2 link	c.641G>A	p.Gly214Asp	missense_variant	Exon 8 of 8		NP_001161419.1
TIMM17B	NM_001395497.1 link	c.641G>A	p.Gly214Asp	missense_variant	Exon 7 of 7		NP_001382426.1
TIMM17B	NM_005834.5 link	c.491G>A	p.Gly164Asp	missense_variant	Exon 7 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 link	c.491G>A	p.Gly164Asp	missense_variant	Exon 6 of 6		NM_001395498.1	ENSP00000512416.1		O60830-1

Frequencies

GnomAD3 genomes

AF:

0.0000272

AC:

AN:

110376

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:

0.000860

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000764

AC:

AN:

130916

AF XY:

0.0000541

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000833

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000352

AC:

AN:

1052179

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

336961

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25179

American (AMR)

AF:

0.00

AC:

AN:

28806

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16021

East Asian (EAS)

AF:

0.00125

AC:

AN:

29713

South Asian (SAS)

AF:

0.00

AC:

AN:

46537

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38329

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3861

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

819700

Other (OTH)

AF:

0.00

AC:

AN:

44033

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000272

AC:

AN:

110426

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

32982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30472

American (AMR)

AF:

0.00

AC:

AN:

10489

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2604

East Asian (EAS)

AF:

0.000863

AC:

AN:

3477

South Asian (SAS)

AF:

0.00

AC:

AN:

2566

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6009

Middle Eastern (MID)

AF:

0.00

AC:

AN:

210

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52433

Other (OTH)

AF:

0.00

AC:

AN:

1497

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000418

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 08, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.641G>A (p.G214D) alteration is located in exon 8 (coding exon 7) of the TIMM17B gene. This alteration results from a G to A substitution at nucleotide position 641, causing the glycine (G) at amino acid position 214 to be replaced by an aspartic acid (D). 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

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

.;T;.;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.60

.;T;T;T

M_CAP

Pathogenic

0.29

MetaRNN

Benign

0.032

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.0

.;L;.;.

PhyloP100

0.76

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

.;N;N;.

REVEL

Benign

0.090

Sift

Benign

0.047

.;D;D;.

Sift4G

Uncertain

0.020

D;D;D;D

Polyphen

0.0040

.;B;.;.

Vest4

0.21

MVP

0.25

MPC

0.55

ClinPred

0.088

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.24

gMVP

0.81

Mutation Taster

=99/1

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.

X-48893757-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over