rs12009983

Variant names:

• chrX-106818560-A-G
• rs12009983
• NM_017752.3:c.131-103A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_017752.3(TBC1D8B):​c.131-103A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 539,957 control chromosomes in the GnomAD database, including 47 homozygotes. There are 620 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (34 hom., 459 hem., cov: 22)
  • Exomes 𝑓: 0.0015 (13 hom. 161 hem.)
• Consequence: TBC1D8B NM_017752.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.76
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant X-106818560-A-G is Benign according to our data. Variant chrX-106818560-A-G is described in ClinVar as [Benign]. Clinvar id is 1226609.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0147 (1643/111398) while in subpopulation AFR AF = 0.0507 (1562/30788). AF 95% confidence interval is 0.0486. There are 34 homozygotes in GnomAd4. There are 459 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1643 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBC1D8B	NM_017752.3	c.131-103A>G		intron_variant	Intron 1 of 20	ENST00000357242.10	NP_060222.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBC1D8B	ENST00000357242.10	c.131-103A>G		intron_variant	Intron 1 of 20	1	NM_017752.3	ENSP00000349781.5

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 1639 AN: 111348 Hom.: 34 Cov.: 22

Gnomad AFR AF: 0.0507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00535

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.000189

Gnomad OTH AF: 0.00874

GnomAD4 exome AF: 0.00153 AC: 657 AN: 428559 Hom.: 13 Cov.: 7 AF XY: 0.00153 AC XY: 161 AN XY: 104993

African (AFR) AF: 0.0485 AC: 495 AN: 10205

American (AMR) AF: 0.00292 AC: 41 AN: 14043

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10273

East Asian (EAS) AF: 0.00 AC: 0 AN: 21978

South Asian (SAS) AF: 0.000312 AC: 5 AN: 16032

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27094

Middle Eastern (MID) AF: 0.00191 AC: 4 AN: 2095

European-Non Finnish (NFE) AF: 0.000105 AC: 32 AN: 305041

Other (OTH) AF: 0.00367 AC: 80 AN: 21798

GnomAD4 genome AF: 0.0147 AC: 1643 AN: 111398 Hom.: 34 Cov.: 22 AF XY: 0.0136 AC XY: 459 AN XY: 33738

African (AFR) AF: 0.0507 AC: 1562 AN: 30788

American (AMR) AF: 0.00535 AC: 56 AN: 10473

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2631

East Asian (EAS) AF: 0.00 AC: 0 AN: 3570

South Asian (SAS) AF: 0.00 AC: 0 AN: 2666

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6055

Middle Eastern (MID) AF: 0.00930 AC: 2 AN: 215

European-Non Finnish (NFE) AF: 0.000189 AC: 10 AN: 52808

Other (OTH) AF: 0.00863 AC: 13 AN: 1507

Alfa AF: 0.0134 Hom.: 59

Bravo AF: 0.0174

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 25, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.67
PhyloP100		1.8
PromoterAI		-0.0061	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs12009983; hg19: chrX-106061790;