X-48893769-G-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001395498.1(TIMM17B):c.479C>A(p.Thr160Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000528 in 1,167,910 control chromosomes in the GnomAD database, including 4 homozygotes. There are 313 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., 7 hem., cov: 23)
  • Exomes 𝑓: 0.00055 (4 hom. 306 hem.)
• Consequence: TIMM17B NM_001395498.1 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.04

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 Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004162401).
• BP6: Variant X-48893769-G-T is Benign according to our data. Variant chrX-48893769-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2660480.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMM17B	NM_001395498.1	c.479C>A	p.Thr160Asn	missense_variant	6/6	ENST00000696123.1
TIMM17B	NM_001167947.2	c.629C>A	p.Thr210Asn	missense_variant	8/8
TIMM17B	NM_001395497.1	c.629C>A	p.Thr210Asn	missense_variant	7/7
TIMM17B	NM_005834.5	c.479C>A	p.Thr160Asn	missense_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMM17B	ENST00000696123.1	c.479C>A	p.Thr160Asn	missense_variant	6/6		NM_001395498.1	P1

Frequencies

GnomAD3 genomes AF: 0.000277 AC: 31 AN: 111792 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 33976

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00791

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00837

Gnomad NFE AF: 0.0000945

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000722 AC: 98 AN: 135666 Hom.: 0 AF XY: 0.00105 AC XY: 41 AN XY: 38966

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000471

Gnomad ASJ exome AF: 0.000271

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00809

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000212

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000555 AC: 586 AN: 1056067 Hom.: 4 Cov.: 30 AF XY: 0.000903 AC XY: 306 AN XY: 338923

Gnomad4 AFR exome AF: 0.0000394

Gnomad4 AMR exome AF: 0.0000335

Gnomad4 ASJ exome AF: 0.0000616

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00935

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.000700

GnomAD4 genome AF: 0.000277 AC: 31 AN: 111843 Hom.: 0 Cov.: 23 AF XY: 0.000206 AC XY: 7 AN XY: 34037

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00114

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00793

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000945

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000117

ExAC AF: 0.00125 AC: 150

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2023

TIMM17B: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-0.92
Cadd	Benign	7.4
Dann	Benign	0.64
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0042	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.0040	.;B;.;.
Vest4		0.11
MutPred		0.21		.;Loss of phosphorylation at T160 (P = 0.0013);.;.;
MVP		0.18
MPC		0.48
ClinPred		0.011	T
GERP RS		3.2
Varity_R		0.046
gMVP		0.44

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

Other links and lift over

dbSNP: rs782624478; hg19: chrX-48751052;