X-48895094-C-A

Variant names:

• chrX-48895094-C-A
• rs781920385
• NM_001395498.1:c.134G>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: TIMM17B NM_001395498.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.808
• Publications: 0 publications found

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]

PQBP1 Gene-Disease associations (from GenCC):

• Renpenning syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• 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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26796585).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395498.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM17B	NM_001395498.1	MANE Select	c.134G>T	p.Arg45Leu	missense	Exon 3 of 6	NP_001382427.1	O60830-1
	TIMM17B	NM_001167947.2		c.284G>T	p.Arg95Leu	missense	Exon 5 of 8	NP_001161419.1	O60830-2
	TIMM17B	NM_001395497.1		c.284G>T	p.Arg95Leu	missense	Exon 4 of 7	NP_001382426.1	O60830-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM17B	ENST00000696123.1	MANE Select	c.134G>T	p.Arg45Leu	missense	Exon 3 of 6	ENSP00000512416.1	O60830-1
	TIMM17B	ENST00000376582.7	TSL:1	c.134G>T	p.Arg45Leu	missense	Exon 4 of 7	ENSP00000365766.3	O60830-1
	TIMM17B	ENST00000920116.1		c.551G>T	p.Arg184Leu	missense	Exon 4 of 7	ENSP00000590175.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.22e-7 AC: 1 AN: 1084105 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 352207

African (AFR) AF: 0.00 AC: 0 AN: 26118

American (AMR) AF: 0.00 AC: 0 AN: 33337

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18865

East Asian (EAS) AF: 0.00 AC: 0 AN: 29903

South Asian (SAS) AF: 0.00 AC: 0 AN: 51571

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39686

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4097

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835003

Other (OTH) AF: 0.00 AC: 0 AN: 45525

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.81
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.20
Sift	Benign	0.26	T
Sift4G	Benign	0.58	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	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.87
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs781920385; hg19: chrX-48752377;