dbSNP rs781920385: TIMM17B:p.Arg45Leu (chrX-48895094-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001395498.1(TIMM17B):c.134G>T(p.Arg45Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,105 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. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.2e-7 ( 0 hom. 0 hem. )

Consequence

TIMM17B
NM_001395498.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.808

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26796585).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TIMM17B	NM_001395498.1 link	c.134G>T	p.Arg45Leu	missense_variant	Exon 3 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2 link	c.284G>T	p.Arg95Leu	missense_variant	Exon 5 of 8		NP_001161419.1
TIMM17B	NM_001395497.1 link	c.284G>T	p.Arg95Leu	missense_variant	Exon 4 of 7		NP_001382426.1
TIMM17B	NM_005834.5 link	c.134G>T	p.Arg45Leu	missense_variant	Exon 4 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1 link	c.134G>T	p.Arg45Leu	missense_variant	Exon 3 of 6		NM_001395498.1	ENSP00000512416.1		O60830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.22e-7

AC:

AN:

1084105

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

352207

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000120

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.23

.;T;.;T;T

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.61

.;T;D;D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.27

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.2

.;L;.;.;.

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-2.9

.;D;D;.;.

REVEL

Benign

0.20

Sift

Benign

0.26

.;T;T;.;.

Sift4G

Benign

0.58

T;T;T;T;T

Polyphen

0.012

.;B;.;.;.

Vest4

0.52

MutPred

0.61

.;Loss of methylation at R45 (P = 0.0198);.;.;.;

MVP

0.22

MPC

0.77

ClinPred

0.89

GERP RS

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.25

gMVP

0.87

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over