NM_017752.3:c.176A>C

Variant names:

• chrX-106818708-A-C
• NM_017752.3:c.176A>C

Variant summary

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

The NM_017752.3(TBC1D8B):​c.176A>C​(p.Lys59Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K59E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 22)
• Consequence: TBC1D8B NM_017752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25
• Publications: 0 publications found

Genes affected

TBC1D8B (HGNC:24715): (TBC1 domain family member 8B) This gene encodes a protein with a TBC (Tre-2/Bub2/CDC16) domain. Some mammalian proteins with this domain have been shown to function as Rab-GAPs by binding to specific Rab proteins and affecting their GTPase activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2011]

MORC4 (HGNC:23485): (MORC family CW-type zinc finger 4) In human, the four current members of the microrchidia (morc) gene family share an N-terminal ATPase-like ATP-binding region and a CW four-cysteine zinc-finger motif. The protein encoded by this gene also has a nuclear matrix binding domain and a two-stranded coiled-coil motif near its C-terminus. This gene is widely expressed at low levels in normal tissues and has elevated expression in placenta and testis. Alternative splicing results in multiple transcript variants encoding distinct proteins. [provided by RefSeq, Jan 2010]

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=0.31628314).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017752.3. 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
	TBC1D8B	NM_017752.3	MANE Select	c.176A>C	p.Lys59Thr	missense	Exon 2 of 21	NP_060222.2
	TBC1D8B	NM_001441214.1		c.176A>C	p.Lys59Thr	missense	Exon 2 of 20	NP_001428143.1
	TBC1D8B	NM_198881.2		c.176A>C	p.Lys59Thr	missense	Exon 2 of 12	NP_942582.1	Q0IIM8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8B	ENST00000357242.10	TSL:1 MANE Select	c.176A>C	p.Lys59Thr	missense	Exon 2 of 21	ENSP00000349781.5	Q0IIM8-1
	TBC1D8B	ENST00000310452.6	TSL:1	c.176A>C	p.Lys59Thr	missense	Exon 2 of 12	ENSP00000310675.2	Q0IIM8-3
	TBC1D8B	ENST00000481617.6	TSL:1	c.176A>C	p.Lys59Thr	missense	Exon 2 of 7	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.085	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.2
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.070	T
Polyphen		1.0	D
Vest4		0.48
MutPred		0.46		Loss of ubiquitination at K59 (P = 0.0167)
MVP		0.33
MPC		0.45
ClinPred		0.98	D
GERP RS		5.8
PromoterAI		0.030	Neutral
Varity_R		0.71
gMVP		0.74
Mutation Taster		=58/42	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

hg19: chrX-106061938;