chrX-106818756-A-G

Variant names:

• chrX-106818756-A-G
• rs1200901251
• NM_017752.3:c.224A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_017752.3(TBC1D8B):​c.224A>G​(p.Tyr75Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000827 in 1,088,220 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts 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. Y75S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000083 (0 hom. 5 hem.)
• Consequence: TBC1D8B NM_017752.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.16
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41223216).
• BS2: High AC in GnomAdExome4 at 9 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.224A>G	p.Tyr75Cys	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>G	p.Tyr75Cys	missense_variant	Exon 2 of 21	1	NM_017752.3	ENSP00000349781.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000111 AC: 2 AN: 179644 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000827 AC: 9 AN: 1088220 Hom.: 0 Cov.: 27 AF XY: 0.0000141 AC XY: 5 AN XY: 354768

African (AFR) AF: 0.00 AC: 0 AN: 26136

American (AMR) AF: 0.00 AC: 0 AN: 34943

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19198

East Asian (EAS) AF: 0.00 AC: 0 AN: 30094

South Asian (SAS) AF: 0.000169 AC: 9 AN: 53264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40196

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4094

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 834544

Other (OTH) AF: 0.00 AC: 0 AN: 45751

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.41	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M;M;.;.
PhyloP100		7.2
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Benign	0.24
Sift	Benign	0.045	D;T;T;D
Sift4G	Benign	0.084	T;T;D;T
Polyphen		1.0	D;.;B;.
Vest4		0.68
MutPred		0.47		Gain of catalytic residue at L76 (P = 0.0118);Gain of catalytic residue at L76 (P = 0.0118);Gain of catalytic residue at L76 (P = 0.0118);Gain of catalytic residue at L76 (P = 0.0118);
MVP		0.30
MPC		0.12
ClinPred		0.71	D
GERP RS		4.7
PromoterAI		0.012	Neutral
Varity_R		0.58
gMVP		0.72
Mutation Taster		=42/58	disease causing

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: rs1200901251; hg19: chrX-106061986;