NM_017752.3:c.131-7A>G

Variant names:

• chrX-106818656-A-G
• rs12010840
• NM_017752.3:c.131-7A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0002370
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.431
• 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.131-7A>G		splice_region_variant, intron_variant	Intron 1 of 20	ENST00000357242.10	NP_060222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.131-7A>G		splice_region_variant, intron_variant	Intron 1 of 20	1	NM_017752.3	ENSP00000349781.5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1633 AN: 111105 Hom.: 35 Cov.: 22

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

GnomAD2 exomes AF: 0.00438 AC: 731 AN: 167082 AF XY: 0.00270

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 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

African (AFR) AF: 0.0538 AC: 1357 AN: 25240

American (AMR) AF: 0.00246 AC: 81 AN: 32903

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18671

East Asian (EAS) AF: 0.00 AC: 0 AN: 29790

South Asian (SAS) AF: 0.000305 AC: 15 AN: 49249

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40071

Middle Eastern (MID) AF: 0.00273 AC: 11 AN: 4025

European-Non Finnish (NFE) AF: 0.0000658 AC: 54 AN: 821260

Other (OTH) AF: 0.00339 AC: 152 AN: 44873

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

African (AFR) AF: 0.0507 AC: 1557 AN: 30713

American (AMR) AF: 0.00520 AC: 54 AN: 10384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00 AC: 0 AN: 2664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6010

Middle Eastern (MID) AF: 0.00935 AC: 2 AN: 214

European-Non Finnish (NFE) AF: 0.000189 AC: 10 AN: 52805

Other (OTH) AF: 0.00938 AC: 14 AN: 1492

Alfa AF: 0.00745 Hom.: 83

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

Dec 23, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

TBC1D8B-related disorder Benign:1

Dec 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-0.43
PromoterAI		0.011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12010840; hg19: chrX-106061886;