Genetic Variant TBC1D8B:c.242-6A>C (chrX-106820871-A-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_017752.3(TBC1D8B):c.242-6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000094 in 1,138,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 58 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 Likely benign (no stars).

Frequency

Genomes: 𝑓 0.000062 ( 0 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.000097 ( 0 hom. 52 hem. )

Consequence

TBC1D8B
NM_017752.3 splice_region, intron

Scores

Splicing: ADA: 0.00003646

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.131

Publications

0 publications found

Variant links:

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]

TBC1D8B links:

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]

MORC4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant X-106820871-A-C is Benign according to our data. Variant chrX-106820871-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 3036227.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000625 (7/112062) while in subpopulation SAS AF = 0.0026 (7/2695). AF 95% confidence interval is 0.00122. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High AC in GnomAd4 at 7 XL,AD gene.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
TBC1D8B	NM_017752.3	MANE Select	c.242-6A>C	splice_region intron	N/A	NP_060222.2
TBC1D8B	NM_001441214.1		c.242-6A>C	splice_region intron	N/A	NP_001428143.1
TBC1D8B	NM_001441215.1		c.-53-6A>C	splice_region intron	N/A	NP_001428144.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TBC1D8B	ENST00000357242.10	TSL:1 MANE Select	c.242-6A>C	splice_region intron	N/A	ENSP00000349781.5	Q0IIM8-1
TBC1D8B	ENST00000310452.6	TSL:1	c.242-6A>C	splice_region intron	N/A	ENSP00000310675.2	Q0IIM8-3
TBC1D8B	ENST00000481617.6	TSL:1	c.242-6A>C	splice_region intron	N/A	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes

AF:

0.0000714

AC:

AN:

112008

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00296

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000225

AC:

AN:

155840

AF XY:

0.000404

show subpopulations

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:

0.0000975

AC:

100

AN:

1026064

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

AN XY:

312496

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23893

American (AMR)

AF:

0.00

AC:

AN:

29386

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18474

East Asian (EAS)

AF:

0.00

AC:

AN:

28798

South Asian (SAS)

AF:

0.00202

AC:

AN:

46606

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40297

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3753

European-Non Finnish (NFE)

AF:

0.00000379

AC:

AN:

791372

Other (OTH)

AF:

0.0000690

AC:

AN:

43485

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000625

AC:

AN:

112062

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

34342

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30978

American (AMR)

AF:

0.00

AC:

AN:

10523

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3586

South Asian (SAS)

AF:

0.00260

AC:

AN:

2695

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53018

Other (OTH)

AF:

0.00

AC:

AN:

1524

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000509

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TBC1D8B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

1.7

(source)

DANN

Benign

0.92

PhyloP100

-0.13

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.036

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over