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. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 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
• 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]

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

Our verdict: Benign. The variant received -10 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 the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 6 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.245C>A	p.Ala82Asp	missense	Exon 3 of 21	NP_060222.2
	TBC1D8B	NM_001441214.1		c.245C>A	p.Ala82Asp	missense	Exon 3 of 20	NP_001428143.1
	TBC1D8B	NM_198881.2		c.245C>A	p.Ala82Asp	missense	Exon 3 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.245C>A	p.Ala82Asp	missense	Exon 3 of 21	ENSP00000349781.5	Q0IIM8-1
	TBC1D8B	ENST00000310452.6	TSL:1	c.245C>A	p.Ala82Asp	missense	Exon 3 of 12	ENSP00000310675.2	Q0IIM8-3
	TBC1D8B	ENST00000481617.6	TSL:1	c.245C>A	p.Ala82Asp	missense	Exon 3 of 7	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes AF: 0.0000180 AC: 2 AN: 111183 Hom.: 0 Cov.: 23

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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 158912 AF XY: 0.00

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

African (AFR) AF: 0.00 AC: 0 AN: 24620

American (AMR) AF: 0.00 AC: 0 AN: 30783

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18715

East Asian (EAS) AF: 0.00 AC: 0 AN: 28787

South Asian (SAS) AF: 0.000126 AC: 6 AN: 47703

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40289

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3850

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813033

Other (OTH) AF: 0.00 AC: 0 AN: 44328

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

African (AFR) AF: 0.00 AC: 0 AN: 30714

American (AMR) AF: 0.00 AC: 0 AN: 10451

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2629

East Asian (EAS) AF: 0.00 AC: 0 AN: 3557

South Asian (SAS) AF: 0.000754 AC: 2 AN: 2654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6015

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52804

Other (OTH) AF: 0.00 AC: 0 AN: 1508

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Nephrotic syndrome, type 20 (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.17
Sift	Benign	0.050	D
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.23
MutPred		0.36		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
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs756459601; hg19: chrX-106064110;