chrX-106822192-G-A

Variant names:

• chrX-106822192-G-A
• rs748366693
• NM_017752.3:c.576G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_017752.3(TBC1D8B):​c.576G>A​(p.Leu192Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,197,652 control chromosomes in the GnomAD database, including 1 homozygotes. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000042 (1 hom. 15 hem.)
• Consequence: TBC1D8B NM_017752.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.73
• 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]

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant X-106822192-G-A is Benign according to our data. Variant chrX-106822192-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2661141.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 46 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.576G>A	p.Leu192Leu	synonymous	Exon 4 of 21	NP_060222.2
	TBC1D8B	NM_001441214.1		c.576G>A	p.Leu192Leu	synonymous	Exon 4 of 20	NP_001428143.1
	TBC1D8B	NM_001441215.1		c.282G>A	p.Leu94Leu	synonymous	Exon 4 of 21	NP_001428144.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBC1D8B	ENST00000357242.10	TSL:1 MANE Select	c.576G>A	p.Leu192Leu	synonymous	Exon 4 of 21	ENSP00000349781.5	Q0IIM8-1
	TBC1D8B	ENST00000310452.6	TSL:1	c.576G>A	p.Leu192Leu	synonymous	Exon 4 of 12	ENSP00000310675.2	Q0IIM8-3
	TBC1D8B	ENST00000481617.6	TSL:1	c.576G>A	p.Leu192Leu	synonymous	Exon 4 of 7	ENSP00000421375.1	D6RFZ2

Frequencies

GnomAD3 genomes AF: 0.0000270 AC: 3 AN: 111053 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000567

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000756 AC: 13 AN: 171874 AF XY: 0.000135

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000239

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000768

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000423 AC: 46 AN: 1086599 Hom.: 1 Cov.: 29 AF XY: 0.0000423 AC XY: 15 AN XY: 354973

African (AFR) AF: 0.00 AC: 0 AN: 25705

American (AMR) AF: 0.000150 AC: 5 AN: 33273

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18829

East Asian (EAS) AF: 0.00 AC: 0 AN: 30097

South Asian (SAS) AF: 0.0000195 AC: 1 AN: 51289

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40259

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 0.0000418 AC: 35 AN: 837551

Other (OTH) AF: 0.000110 AC: 5 AN: 45532

GnomAD4 genome AF: 0.0000270 AC: 3 AN: 111053 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 33379

African (AFR) AF: 0.00 AC: 0 AN: 30562

American (AMR) AF: 0.00 AC: 0 AN: 10407

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2626

East Asian (EAS) AF: 0.00 AC: 0 AN: 3534

South Asian (SAS) AF: 0.00 AC: 0 AN: 2665

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5941

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000567 AC: 3 AN: 52903

Other (OTH) AF: 0.00 AC: 0 AN: 1490

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000604

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	6.6
DANN	Benign	0.75
PhyloP100		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs748366693; hg19: chrX-106065422;