X-106802972-G-T

Variant names:

• chrX-106802972-G-T
• rs754093308
• NM_017752.3:c.119G>T

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.119G>T​(p.Gly40Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000034 in 1,204,856 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 𝑓 0.000045 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 12 hem.)
• Consequence: TBC1D8B NM_017752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.05
• 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]

TBC1D8B Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 20

  Inheritance: XL Classification: STRONG, MODERATE, LIMITED Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, Ambry Genetics
• 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=0.21612483).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0000447 (5/111962) while in subpopulation AMR AF = 0.000471 (5/10619). AF 95% confidence interval is 0.000185. There are 0 homozygotes in GnomAd4. There are 0 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 5 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8B	NM_017752.3	MANE Select	c.119G>T	p.Gly40Val	missense	Exon 1 of 21	NP_060222.2
	TBC1D8B	NM_001441214.1		c.119G>T	p.Gly40Val	missense	Exon 1 of 20	NP_001428143.1
	TBC1D8B	NM_198881.2		c.119G>T	p.Gly40Val	missense	Exon 1 of 12	NP_942582.1	Q0IIM8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8B	ENST00000357242.10	TSL:1 MANE Select	c.119G>T	p.Gly40Val	missense	Exon 1 of 21	ENSP00000349781.5	Q0IIM8-1
	TBC1D8B	ENST00000310452.6	TSL:1	c.119G>T	p.Gly40Val	missense	Exon 1 of 12	ENSP00000310675.2	Q0IIM8-3
	TBC1D8B	ENST00000481617.6	TSL:1	c.119G>T	p.Gly40Val	missense	Exon 1 of 7	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes AF: 0.0000447 AC: 5 AN: 111962 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000185 AC: 32 AN: 172886 AF XY: 0.000185

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00101

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: 0.00117

GnomAD4 exome AF: 0.0000329 AC: 36 AN: 1092894 Hom.: 0 Cov.: 30 AF XY: 0.0000334 AC XY: 12 AN XY: 358966

African (AFR) AF: 0.00 AC: 0 AN: 26360

American (AMR) AF: 0.000915 AC: 32 AN: 34957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19117

East Asian (EAS) AF: 0.00 AC: 0 AN: 30134

South Asian (SAS) AF: 0.00 AC: 0 AN: 53053

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3984

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 840109

Other (OTH) AF: 0.0000654 AC: 3 AN: 45892

GnomAD4 genome AF: 0.0000447 AC: 5 AN: 111962 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34100

African (AFR) AF: 0.00 AC: 0 AN: 30799

American (AMR) AF: 0.000471 AC: 5 AN: 10619

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2679

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6111

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53130

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000718

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.088	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.28
Sift	Uncertain	0.029	D
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.43		Loss of disorder (P = 0.0198)
MVP		0.42
MPC		0.47
ClinPred		0.18	T
GERP RS		5.2
PromoterAI		-0.030	Neutral
Varity_R		0.72
gMVP		0.50
Mutation Taster		=92/8	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: rs754093308; hg19: chrX-106046202;