chrX-48893757-C-G

Variant names:

• chrX-48893757-C-G
• rs180854016
• NM_001395498.1:c.491G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001395498.1(TIMM17B):​c.491G>C​(p.Gly164Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,052,183 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 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: 0.0000019 (0 hom. 1 hem.)
• Consequence: TIMM17B NM_001395498.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.757

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16679516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM17B	NM_001395498.1	c.491G>C	p.Gly164Ala	missense_variant	Exon 6 of 6	ENST00000696123.1	NP_001382427.1
TIMM17B	NM_001167947.2	c.641G>C	p.Gly214Ala	missense_variant	Exon 8 of 8		NP_001161419.1
TIMM17B	NM_001395497.1	c.641G>C	p.Gly214Ala	missense_variant	Exon 7 of 7		NP_001382426.1
TIMM17B	NM_005834.5	c.491G>C	p.Gly164Ala	missense_variant	Exon 7 of 7		NP_005825.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM17B	ENST00000696123.1	c.491G>C	p.Gly164Ala	missense_variant	Exon 6 of 6		NM_001395498.1	ENSP00000512416.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000190 AC: 2 AN: 1052183 Hom.: 0 Cov.: 29 AF XY: 0.00000297 AC XY: 1 AN XY: 336965

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000673

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.047	.;T;.;T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	.;T;T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.17	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	.;L;.;.
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	.;N;N;.
REVEL	Benign	0.14
Sift	Benign	0.32	.;T;T;.
Sift4G	Benign	0.096	T;T;T;T
Polyphen		0.58	.;P;.;.
Vest4		0.21
MutPred		0.076		.;Gain of glycosylation at P161 (P = 0.0903);.;.;
MVP		0.26
MPC		0.68
ClinPred		0.28	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.73

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: rs180854016; hg19: chrX-48751040;