NM_017752.3:c.119G>C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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. G40V) 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
• Clinical Significance: Not reported in ClinVar
• 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: 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).

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>C	p.Gly40Ala	missense	Exon 1 of 21	NP_060222.2
	TBC1D8B	NM_001441214.1		c.119G>C	p.Gly40Ala	missense	Exon 1 of 20	NP_001428143.1
	TBC1D8B	NM_198881.2		c.119G>C	p.Gly40Ala	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>C	p.Gly40Ala	missense	Exon 1 of 21	ENSP00000349781.5	Q0IIM8-1
	TBC1D8B	ENST00000310452.6	TSL:1	c.119G>C	p.Gly40Ala	missense	Exon 1 of 12	ENSP00000310675.2	Q0IIM8-3
	TBC1D8B	ENST00000481617.6	TSL:1	c.119G>C	p.Gly40Ala	missense	Exon 1 of 7	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000578 AC: 1 AN: 172886 AF XY: 0.0000168

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: 3 AN: 1092894 Hom.: 0 Cov.: 30 AF XY: 0.00000279 AC XY: 1 AN XY: 358966

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

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

American (AMR) AF: 0.00 AC: 0 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: 0.0000565 AC: 3 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: 0.00 AC: 0 AN: 840109

Other (OTH) AF: 0.00 AC: 0 AN: 45892

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.15
Sift	Benign	0.14	T
Sift4G	Uncertain	0.016	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.38		Loss of disorder (P = 0.0666)
MVP		0.43
MPC		0.17
ClinPred		0.62	D
GERP RS		5.2
PromoterAI		-0.030	Neutral
Varity_R		0.46
gMVP		0.44
Mutation Taster		=95/5	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;