X-48894169-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001395498.1(TIMM17B):c.247C>T(p.Leu83Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000915 in 1,093,234 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

TIMM17B
NM_001395498.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.511

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20080513).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMM17B	NM_001395498.1 link	c.247C>T	p.Leu83Phe	missense_variant	Exon 4 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2 link	c.397C>T	p.Leu133Phe	missense_variant	Exon 6 of 8		NP_001161419.1
TIMM17B	NM_001395497.1 link	c.397C>T	p.Leu133Phe	missense_variant	Exon 5 of 7		NP_001382426.1
TIMM17B	NM_005834.5 link	c.247C>T	p.Leu83Phe	missense_variant	Exon 5 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 link	c.247C>T	p.Leu83Phe	missense_variant	Exon 4 of 6		NM_001395498.1	ENSP00000512416.1		O60830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000583

AC:

AN:

171502

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000833

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

9.15e-7

AC:

AN:

1093234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

359350

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000380

AC:

AN:

26305

American (AMR)

AF:

0.00

AC:

AN:

34833

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19273

East Asian (EAS)

AF:

0.00

AC:

AN:

30052

South Asian (SAS)

AF:

0.00

AC:

AN:

53415

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40205

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

839183

Other (OTH)

AF:

0.00

AC:

AN:

45836

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 18, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.397C>T (p.L133F) alteration is located in exon 6 (coding exon 5) of the TIMM17B gene. This alteration results from a C to T substitution at nucleotide position 397, causing the leucine (L) at amino acid position 133 to be replaced by a phenylalanine (F). 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

0.11

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.047

.;T;.;T;T

FATHMM_MKL

Benign

0.12

LIST_S2

Uncertain

0.94

.;D;D;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.20

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

.;L;.;.;.

PhyloP100

0.51

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.2

.;N;N;.;.

REVEL

Benign

0.081

Sift

Benign

0.30

.;T;T;.;.

Sift4G

Benign

0.26

T;T;T;T;T

Polyphen

0.41

.;B;.;.;.

Vest4

0.38

MutPred

0.42

.;Loss of ubiquitination at K86 (P = 0.0982);.;.;.;

MVP

0.47

MPC

1.1

ClinPred

0.097

GERP RS

1.5

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.1

Varity_R

0.12

gMVP

0.94

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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-48894169-G-A

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