X-48894195-G-C

Variant names:

• chrX-48894195-G-C
• NM_001395498.1:c.221C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001395498.1(TIMM17B):​c.221C>G​(p.Ser74Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,095,055 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 1 hem.)
• Consequence: TIMM17B NM_001395498.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, ClinGen
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.97

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM17B	NM_001395498.1	c.221C>G	p.Ser74Cys	missense_variant	Exon 4 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2	c.371C>G	p.Ser124Cys	missense_variant	Exon 6 of 8		NP_001161419.1
TIMM17B	NM_001395497.1	c.371C>G	p.Ser124Cys	missense_variant	Exon 5 of 7		NP_001382426.1
TIMM17B	NM_005834.5	c.221C>G	p.Ser74Cys	missense_variant	Exon 5 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1	c.221C>G	p.Ser74Cys	missense_variant	Exon 4 of 6		NM_001395498.1	ENSP00000512416.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000548 AC: 6 AN: 1095055 Hom.: 0 Cov.: 31 AF XY: 0.00000277 AC XY: 1 AN XY: 360855

African (AFR) AF: 0.00 AC: 0 AN: 26352

American (AMR) AF: 0.00 AC: 0 AN: 34973

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19309

East Asian (EAS) AF: 0.00 AC: 0 AN: 30122

South Asian (SAS) AF: 0.00 AC: 0 AN: 53646

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.00000714 AC: 6 AN: 840236

Other (OTH) AF: 0.00 AC: 0 AN: 45944

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371C>G (p.S124C) alteration is located in exon 6 (coding exon 5) of the TIMM17B gene. This alteration results from a C to G substitution at nucleotide position 371, causing the serine (S) at amino acid position 124 to be replaced by a cysteine (C). 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	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	.;T;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D;D;D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	3.0	.;M;.;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.9	.;D;D;.;.
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	.;D;D;.;.
Sift4G	Pathogenic	0.0010	D;D;D;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.91
MutPred		0.87		.;Loss of MoRF binding (P = 0.2375);.;.;.;
MVP		0.65
MPC		1.2
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.93
gMVP		0.99
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chrX-48751478;