Genetic Variant TBC1D8B:p.Gly40Ala (chrX-106802972-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017752.3(TBC1D8B):c.119G>C(p.Gly40Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,092,894 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 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. G40E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )

Consequence

TBC1D8B
NM_017752.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.05

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 Gene-Disease associations (from GenCC):

nephrotic syndrome, type 20
Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TBC1D8B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25771263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3 link	c.119G>C	p.Gly40Ala	missense_variant	Exon 1 of 21	ENST00000357242.10	NP_060222.2	Q0IIM8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TBC1D8B	ENST00000357242.10 link	c.119G>C	p.Gly40Ala	missense_variant	Exon 1 of 21	1	NM_017752.3	ENSP00000349781.5	Q0IIM8-1
TBC1D8B	ENST00000310452.6 link	c.119G>C	p.Gly40Ala	missense_variant	Exon 1 of 12	1		ENSP00000310675.2	Q0IIM8-3
TBC1D8B	ENST00000481617.6 link	c.119G>C	p.Gly40Ala	missense_variant	Exon 1 of 7	1		ENSP00000421375.1	D6RFZ2
TBC1D8B	ENST00000276175.7 link	c.119G>C	p.Gly40Ala	missense_variant	Exon 1 of 21	5		ENSP00000276175.3	J3KN75

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000578

AC:

AN:

172886

AF XY:

0.0000168

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:

0.00000275

AC:

AN:

1092894

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

358966

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26360

American (AMR)

AF:

0.00

AC:

AN:

34957

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19117

East Asian (EAS)

AF:

0.00

AC:

AN:

30134

South Asian (SAS)

AF:

0.0000565

AC:

AN:

53053

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3984

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840109

Other (OTH)

AF:

0.00

AC:

AN:

45892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.029673), 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.072

T;.;T;T

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.74

T;T;T;T

M_CAP

Benign

0.030

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.4

M;M;.;.

PhyloP100

9.1

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.2

N;D;D;N

REVEL

Benign

0.15

Sift

Benign

0.14

T;T;T;T

Sift4G

Uncertain

0.016

D;D;D;D

Polyphen

1.0

D;.;P;.

Vest4

0.48

MutPred

0.38

Loss of disorder (P = 0.0666);Loss of disorder (P = 0.0666);Loss of disorder (P = 0.0666);Loss of disorder (P = 0.0666);

MVP

0.43

MPC

0.17

ClinPred

0.62

GERP RS

5.2

PromoterAI

-0.030

Neutral

(source)

Varity_R

0.46

gMVP

0.44

Mutation Taster

=95/5

polymorphism

(source)

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

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X-106802972-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over