X-48897739-T-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_001395498.1(TIMM17B):c.11A>T(p.Tyr4Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000348 in 1,208,394 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 6 hem., cov: 24)

Exomes 𝑓: 0.000020 ( 0 hom. 7 hem. )

Consequence

TIMM17B
NM_001395498.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.40

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.28078967).

BS2

High Hemizygotes in GnomAd4 at 6 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM17B	NM_001395498.1 link	c.11A>T	p.Tyr4Phe	missense_variant	Exon 1 of 6	ENST00000696123.1	NP_001382427.1
PQBP1	NM_001032382.2 link	c.-362T>A		upstream_gene_variant		ENST00000447146.7	NP_001027554.1	O60828-1A0A0S2Z4V5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 link	c.11A>T	p.Tyr4Phe	missense_variant	Exon 1 of 6		NM_001395498.1	ENSP00000512416.1		O60830-1
PQBP1	ENST00000447146.7 link	c.-362T>A		upstream_gene_variant		1	NM_001032382.2	ENSP00000391759.2		O60828-1

Frequencies

GnomAD3 genomes

AF:

0.000178

AC:

AN:

112645

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000645

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00150

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:

0.00

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.0000225

AC:

AN:

178156

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000735

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:

0.000454

GnomAD4 exome

AF:

0.0000201

AC:

AN:

1095695

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

361353

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26365

American (AMR)

AF:

0.000484

AC:

AN:

35154

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19329

East Asian (EAS)

AF:

0.00

AC:

AN:

30176

South Asian (SAS)

AF:

0.00

AC:

AN:

53854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840715

Other (OTH)

AF:

0.0000869

AC:

AN:

46009

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000177

AC:

AN:

112699

Hom.:

Cov.:

AF XY:

0.000172

AC XY:

AN XY:

34847

show subpopulations

African (AFR)

AF:

0.0000643

AC:

AN:

31086

American (AMR)

AF:

0.00149

AC:

AN:

10714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.00

AC:

AN:

2783

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6209

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53254

Other (OTH)

AF:

0.00131

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000540

ExAC

AF:

0.00000825

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.11A>T (p.Y4F) alteration is located in exon 2 (coding exon 1) of the TIMM17B gene. This alteration results from a A to T substitution at nucleotide position 11, causing the tyrosine (Y) at amino acid position 4 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

0.30

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.23

.;T;.

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.9

L;L;L

PhyloP100

7.4

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-3.0

.;D;D

REVEL

Benign

0.25

Sift

Benign

0.16

.;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.96

.;P;.

Vest4

0.63

MutPred

0.42

Loss of phosphorylation at Y4 (P = 0.0516);Loss of phosphorylation at Y4 (P = 0.0516);Loss of phosphorylation at Y4 (P = 0.0516);

MVP

0.27

MPC

0.38

ClinPred

0.17

GERP RS

5.6

PromoterAI

-0.037

Neutral

(source)

Varity_R

0.43

gMVP

0.81

Mutation Taster

=228/72

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-48897739-T-A

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