X-106818756-A-C

Variant names:

• chrX-106818756-A-C
• NM_017752.3:c.224A>C

Variant summary

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

The NM_017752.3(TBC1D8B):​c.224A>C​(p.Tyr75Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 7.16

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.224A>C	p.Tyr75Ser	missense_variant	Exon 2 of 21	ENST00000357242.10	NP_060222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.224A>C	p.Tyr75Ser	missense_variant	Exon 2 of 21	1	NM_017752.3	ENSP00000349781.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.224A>C (p.Y75S) alteration is located in exon 2 (coding exon 2) of the TBC1D8B gene. This alteration results from a A to C substitution at nucleotide position 224, causing the tyrosine (Y) at amino acid position 75 to be replaced by a serine (S). 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	Benign	0.22
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.30	T;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.73	D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.9	D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.11	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		1.0	D;.;D;.
Vest4		0.83
MutPred		0.51		Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);Gain of disorder (P = 0.0063);
MVP		0.26
MPC		0.12
ClinPred		0.96	D
GERP RS		4.7
Varity_R		0.72
gMVP		0.75

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-106061986;