NM_017752.3:c.245C>A

Variant names:

• chrX-106820880-C-A
• rs756459601
• NM_017752.3:c.245C>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_017752.3(TBC1D8B):​c.245C>A​(p.Ala82Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,163,343 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.0000057 (0 hom. 3 hem.)
• Consequence: TBC1D8B NM_017752.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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]

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09587476).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000018 (2/111235) while in subpopulation SAS AF= 0.000754 (2/2654). AF 95% confidence interval is 0.000134. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAdExome4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.245C>A	p.Ala82Asp	missense_variant	Exon 3 of 21	ENST00000357242.10	NP_060222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.245C>A	p.Ala82Asp	missense_variant	Exon 3 of 21	1	NM_017752.3	ENSP00000349781.5

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111183 Hom.: 0 Cov.: 23 AF XY: 0.0000298 AC XY: 1 AN XY: 33591

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: 0.000751

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000570 AC: 6 AN: 1052108 Hom.: 0 Cov.: 22 AF XY: 0.00000908 AC XY: 3 AN XY: 330218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000180 AC: 2 AN: 111235 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33653

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000754

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Nephrotic syndrome, type 20 Uncertain:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant c.245C>A (p.Ala82Asp) in TBC1D8B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Ala82Asp variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. The amino acid Ala at position 82 is changed to a Asp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Ala82Asp in TBC1D8B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.082	T;.;T;T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.096	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;M;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N;D;D;N
REVEL	Benign	0.17
Sift	Benign	0.050	D;T;T;T
Sift4G	Benign	0.14	T;T;D;T
Polyphen		1.0	D;.;D;.
Vest4		0.23
MutPred		0.36		Gain of solvent accessibility (P = 0.0202);Gain of solvent accessibility (P = 0.0202);Gain of solvent accessibility (P = 0.0202);Gain of solvent accessibility (P = 0.0202);
MVP		0.26
MPC		0.34
ClinPred		0.72	D
GERP RS		5.1
Varity_R		0.61
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs756459601; hg19: chrX-106064110;