X-48893945-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001395498.1(TIMM17B):​c.385G>A​(p.Val129Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000255 in 1,096,674 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 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 0.000018 ( 0 hom., 1 hem., cov: 23)
Exomes 𝑓: 0.000026 ( 0 hom. 9 hem. )
Failed GnomAD Quality Control

Consequence

TIMM17B
NM_001395498.1 missense

Scores

4
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.96
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.3284304).
BS2
High Hemizygotes in GnomAdExome4 at 9 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TIMM17BNM_001395498.1 linkuse as main transcriptc.385G>A p.Val129Ile missense_variant 5/6 ENST00000696123.1
TIMM17BNM_001167947.2 linkuse as main transcriptc.535G>A p.Val179Ile missense_variant 7/8
TIMM17BNM_001395497.1 linkuse as main transcriptc.535G>A p.Val179Ile missense_variant 6/7
TIMM17BNM_005834.5 linkuse as main transcriptc.385G>A p.Val129Ile missense_variant 6/7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TIMM17BENST00000696123.1 linkuse as main transcriptc.385G>A p.Val129Ile missense_variant 5/6 NM_001395498.1 P1O60830-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
2
AN:
112365
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34545
FAILED QC
Gnomad AFR
AF:
0.00
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:
0.0000376
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000222
AC:
4
AN:
180013
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
64947
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000500
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000255
AC:
28
AN:
1096674
Hom.:
0
Cov.:
30
AF XY:
0.0000249
AC XY:
9
AN XY:
362084
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000371
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000309
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.0000178
AC:
2
AN:
112365
Hom.:
0
Cov.:
23
AF XY:
0.0000289
AC XY:
1
AN XY:
34545
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000376
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingAmbry GeneticsJul 09, 2021The c.535G>A (p.V179I) alteration is located in exon 7 (coding exon 6) of the TIMM17B gene. This alteration results from a G to A substitution at nucleotide position 535, causing the valine (V) at amino acid position 179 to be replaced by an isoleucine (I). 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
0.14
BayesDel_addAF
Benign
-0.38
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
20
DANN
Uncertain
1.0
DEOGEN2
Benign
0.048
.;T;.;T
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.93
.;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.33
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.5
.;L;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-0.61
.;N;N;.
REVEL
Benign
0.079
Sift
Benign
0.16
.;T;D;.
Sift4G
Benign
0.15
T;T;T;T
Polyphen
0.35
.;B;.;.
Vest4
0.29
MutPred
0.65
.;Loss of catalytic residue at V129 (P = 0.2383);.;.;
MVP
0.19
MPC
0.48
ClinPred
0.20
T
GERP RS
4.7
Varity_R
0.17
gMVP
0.76

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.

Other links and lift over

dbSNP: rs782186116; hg19: chrX-48751228; API