chrX-9653599-G-T

Variant names:

• chrX-9653599-G-T
• rs138597617
• NM_005647.4:c.13G>T

Variant summary

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

The NM_005647.4(TBL1X):​c.13G>T​(p.Ala5Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,168,648 control chromosomes in the GnomAD database, including 8 homozygotes. There are 330 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A5P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0050 (4 hom., 161 hem., cov: 23)
  • Exomes 𝑓: 0.00062 (4 hom. 169 hem.)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.57
• Publications: 1 publications found

Genes affected

TBL1X (HGNC:11585): (transducin beta like 1 X-linked) The protein encoded by this gene has sequence similarity with members of the WD40 repeat-containing protein family. The WD40 group is a large family of proteins, which appear to have a regulatory function. It is believed that the WD40 repeats mediate protein-protein interactions and members of the family are involved in signal transduction, RNA processing, gene regulation, vesicular trafficking, cytoskeletal assembly and may play a role in the control of cytotypic differentiation. This encoded protein is found as a subunit in corepressor SMRT (silencing mediator for retinoid and thyroid receptors) complex along with histone deacetylase 3 protein. This gene is located adjacent to the ocular albinism gene and it is thought to be involved in the pathogenesis of the ocular albinism with late-onset sensorineural deafness phenotype. Four transcript variants encoding two different isoforms have been found for this gene. This gene is highly similar to the Y chromosome TBL1Y gene. [provided by RefSeq, Nov 2008]

TBL1X Gene-Disease associations (from GenCC):

• hypothyroidism, congenital, nongoitrous, 8

  Inheritance: Unknown, XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034570694).
• BP6: Variant X-9653599-G-T is Benign according to our data. Variant chrX-9653599-G-T is described in ClinVar as Benign. ClinVar VariationId is 720639.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.005 (564/112741) while in subpopulation AFR AF = 0.0169 (526/31089). AF 95% confidence interval is 0.0157. There are 4 homozygotes in GnomAd4. There are 161 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005647.4. 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
	TBL1X	NM_005647.4	MANE Select	c.13G>T	p.Ala5Ser	missense	Exon 4 of 18	NP_005638.1	O60907-1
	TBL1X	NM_001139466.1		c.13G>T	p.Ala5Ser	missense	Exon 4 of 18	NP_001132938.1	O60907-1
	TBL1X	NM_001139467.1		c.-50-616G>T		intron	N/A	NP_001132939.1	O60907-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TBL1X	ENST00000645353.2	MANE Select	c.13G>T	p.Ala5Ser	missense	Exon 4 of 18	ENSP00000496215.1	O60907-1
	TBL1X	ENST00000380961.5	TSL:1	c.-50-616G>T		intron	N/A	ENSP00000370348.1	O60907-2
	TBL1X	ENST00000407597.7	TSL:2	c.13G>T	p.Ala5Ser	missense	Exon 4 of 18	ENSP00000385988.2	O60907-1

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 564 AN: 112687 Hom.: 4 Cov.: 23

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00224

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000750

Gnomad OTH AF: 0.00593

GnomAD2 exomes AF: 0.00145 AC: 170 AN: 116880 AF XY: 0.000985

Gnomad AFR exome AF: 0.0191

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000438

Gnomad OTH exome AF: 0.000602

GnomAD4 exome AF: 0.000620 AC: 655 AN: 1055907 Hom.: 4 Cov.: 30 AF XY: 0.000490 AC XY: 169 AN XY: 344987

African (AFR) AF: 0.0201 AC: 503 AN: 25010

American (AMR) AF: 0.000916 AC: 26 AN: 28399

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18623

East Asian (EAS) AF: 0.00 AC: 0 AN: 27239

South Asian (SAS) AF: 0.00 AC: 0 AN: 49893

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37658

Middle Eastern (MID) AF: 0.00293 AC: 12 AN: 4094

European-Non Finnish (NFE) AF: 0.0000524 AC: 43 AN: 820506

Other (OTH) AF: 0.00160 AC: 71 AN: 44485

GnomAD4 genome AF: 0.00500 AC: 564 AN: 112741 Hom.: 4 Cov.: 23 AF XY: 0.00461 AC XY: 161 AN XY: 34915

African (AFR) AF: 0.0169 AC: 526 AN: 31089

American (AMR) AF: 0.00224 AC: 24 AN: 10720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3573

South Asian (SAS) AF: 0.00 AC: 0 AN: 2752

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6210

Middle Eastern (MID) AF: 0.00457 AC: 1 AN: 219

European-Non Finnish (NFE) AF: 0.0000750 AC: 4 AN: 53305

Other (OTH) AF: 0.00586 AC: 9 AN: 1536

Alfa AF: 0.000203 Hom.: 7

Bravo AF: 0.00576

ESP6500AA AF: 0.0171 AC: 65

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00135 AC: 136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	TBL1X-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.0020
DANN	Benign	0.77
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Benign	0.0051	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-3.6
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.13
Sift	Benign	0.071	T
Sift4G	Benign	0.15	T
Polyphen		0.0	B
Vest4		0.068
MVP		0.62
MPC		0.66
ClinPred		0.0071	T
GERP RS		-2.6
Varity_R		0.062
gMVP		0.063
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: rs138597617; hg19: chrX-9621639;