X-106818656-A-G

Position:

• chrX-106818656-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017752.3(TBC1D8B):​c.131-7A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,177,240 control chromosomes in the GnomAD database, including 72 homozygotes. There are 868 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (35 hom., 452 hem., cov: 22)
  • Exomes 𝑓: 0.0016 (37 hom. 416 hem.)
• Consequence: TBC1D8B NM_017752.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002370
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.431

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant X-106818656-A-G is Benign according to our data. Variant chrX-106818656-A-G is described in ClinVar as [Benign]. Clinvar id is 1269644.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TBC1D8B	NM_017752.3	c.131-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000357242.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.131-7A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_017752.3	P2

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1633 AN: 111105 Hom.: 35 Cov.: 22 AF XY: 0.0135 AC XY: 450 AN XY: 33441

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00521

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00851

Gnomad NFE AF: 0.000189

Gnomad OTH AF: 0.00951

GnomAD3 exomes AF: 0.00438 AC: 731 AN: 167082 Hom.: 17 AF XY: 0.00270 AC XY: 147 AN XY: 54386

Gnomad AFR exome AF: 0.0537

Gnomad AMR exome AF: 0.00178

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000651

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000104

Gnomad OTH exome AF: 0.00299

GnomAD4 exome AF: 0.00157 AC: 1670 AN: 1066082 Hom.: 37 Cov.: 24 AF XY: 0.00123 AC XY: 416 AN XY: 337642

Gnomad4 AFR exome AF: 0.0538

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000305

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000658

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0147 AC: 1637 AN: 111158 Hom.: 35 Cov.: 22 AF XY: 0.0135 AC XY: 452 AN XY: 33504

Gnomad4 AFR AF: 0.0507

Gnomad4 AMR AF: 0.00520

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000189

Gnomad4 OTH AF: 0.00938

Alfa AF: 0.00689 Hom.: 67

Bravo AF: 0.0174

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2020	- -

TBC1D8B-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.50
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.014
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: rs12010840; hg19: chrX-106061886;