X-106802956-G-C

Variant names:

• chrX-106802956-G-C
• rs756295158
• NM_017752.3:c.103G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_017752.3(TBC1D8B):​c.103G>C​(p.Gly35Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00001 in 1,095,810 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000010 (0 hom. 3 hem.)
• Consequence: TBC1D8B NM_017752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.43
• Publications: 1 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]

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

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14360142).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00001 (11/1095810) while in subpopulation AMR AF = 0.000285 (10/35089). AF 95% confidence interval is 0.000154. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 11 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.103G>C	p.Gly35Arg	missense_variant	Exon 1 of 21	ENST00000357242.10	NP_060222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.103G>C	p.Gly35Arg	missense_variant	Exon 1 of 21	1	NM_017752.3	ENSP00000349781.5
TBC1D8B	ENST00000310452.6	c.103G>C	p.Gly35Arg	missense_variant	Exon 1 of 12	1		ENSP00000310675.2
TBC1D8B	ENST00000481617.6	c.103G>C	p.Gly35Arg	missense_variant	Exon 1 of 7	1		ENSP00000421375.1
TBC1D8B	ENST00000276175.7	c.103G>C	p.Gly35Arg	missense_variant	Exon 1 of 21	5		ENSP00000276175.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000505 AC: 9 AN: 178380 AF XY: 0.0000471

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000332

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: 0.0000100 AC: 11 AN: 1095810 Hom.: 0 Cov.: 30 AF XY: 0.00000830 AC XY: 3 AN XY: 361418

African (AFR) AF: 0.00 AC: 0 AN: 26387

American (AMR) AF: 0.000285 AC: 10 AN: 35089

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19292

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30151

South Asian (SAS) AF: 0.00 AC: 0 AN: 53742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39863

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4047

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841238

Other (OTH) AF: 0.00 AC: 0 AN: 46001

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.103G>C (p.G35R) alteration is located in exon 1 (coding exon 1) of the TBC1D8B gene. This alteration results from a G to C substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.;T;T
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.78	T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.;.
PhyloP100		4.4
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.4	D;D;D;D
REVEL	Benign	0.072
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.020	D;D;D;D
Polyphen		0.015	B;.;B;.
Vest4		0.23
MutPred		0.42		Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);Gain of solvent accessibility (P = 0.0055);
MVP		0.17
MPC		0.11
ClinPred		0.39	T
GERP RS		4.3
PromoterAI		0.032	Neutral
Varity_R		0.33
gMVP		0.55
Mutation Taster		=98/2	polymorphism

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: rs756295158; hg19: chrX-106046186;