X-48894171-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001395498.1(TIMM17B):c.245G>A(p.Arg82Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,205,505 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000015 (0 hom. 7 hem.)
• Consequence: TIMM17B NM_001395498.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.908

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.10329521).
• BS2: High Hemizygotes in GnomAdExome at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM17B	NM_001395498.1	c.245G>A	p.Arg82Gln	missense_variant	4/6	ENST00000696123.1
TIMM17B	NM_001167947.2	c.395G>A	p.Arg132Gln	missense_variant	6/8
TIMM17B	NM_001395497.1	c.395G>A	p.Arg132Gln	missense_variant	5/7
TIMM17B	NM_005834.5	c.245G>A	p.Arg82Gln	missense_variant	5/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMM17B	ENST00000696123.1	c.245G>A	p.Arg82Gln	missense_variant	4/6		NM_001395498.1	P1

Frequencies

GnomAD3 genomes AF: 0.0000716 AC: 8 AN: 111690 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33842

Gnomad AFR AF: 0.0000976

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: 0.0000942

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000290 AC: 5 AN: 172153 Hom.: 0 AF XY: 0.0000511 AC XY: 3 AN XY: 58717

Gnomad AFR exome AF: 0.0000829

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000746

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000398

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000146 AC: 16 AN: 1093815 Hom.: 0 Cov.: 30 AF XY: 0.0000195 AC XY: 7 AN XY: 359869

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000333

Gnomad4 SAS exome AF: 0.0000187

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000716 AC: 8 AN: 111690 Hom.: 0 Cov.: 23 AF XY: 0.0000295 AC XY: 1 AN XY: 33842

Gnomad4 AFR AF: 0.0000976

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: 0.0000942

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.395G>A (p.R132Q) alteration is located in exon 6 (coding exon 5) of the TIMM17B gene. This alteration results from a G to A substitution at nucleotide position 395, causing the arginine (R) at amino acid position 132 to be replaced by a glutamine (Q). 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	0.088
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	13
Dann	Uncertain	1.0
FATHMM_MKL	Benign	0.22	N
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.69	N;N
PrimateAI	Uncertain	0.55	T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.016	.;B;.;.;.
Vest4		0.17
MutPred		0.28		.;Loss of catalytic residue at R82 (P = 0.1135);.;.;.;
MVP		0.15
MPC		0.49
ClinPred		0.048	T
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.11
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs782618036; hg19: chrX-48751454;