rs2239411

Variant names:

• chrX-9697328-C-A
• rs2239411
• NM_005647.4:c.1054-41C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005647.4(TBL1X):​c.1054-41C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.407 in 1,198,530 control chromosomes in the GnomAD database, including 68,741 homozygotes. There are 159,550 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (5311 hom., 11477 hem., cov: 23)
  • Exomes 𝑓: 0.41 (63430 hom. 148073 hem.)
• Consequence: TBL1X NM_005647.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 6 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: XL, Unknown Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-9697328-C-A is Benign according to our data. Variant chrX-9697328-C-A is described in ClinVar as [Benign]. Clinvar id is 1334931.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.428 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.1054-41C>A		intron_variant	Intron 11 of 17	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.1054-41C>A		intron_variant	Intron 11 of 17		NP_001132938.1
TBL1X	NM_001139467.1	c.901-41C>A		intron_variant	Intron 10 of 16		NP_001132939.1
TBL1X	NM_001139468.1	c.901-41C>A		intron_variant	Intron 11 of 17		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.1054-41C>A		intron_variant	Intron 11 of 17		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes AF: 0.350 AC: 38979 AN: 111245 Hom.: 5309 Cov.: 23

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.447

Gnomad AMR AF: 0.437

Gnomad ASJ AF: 0.355

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.425

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.407

Gnomad NFE AF: 0.423

Gnomad OTH AF: 0.381

GnomAD2 exomes AF: 0.384 AC: 66468 AN: 172976 AF XY: 0.386

Gnomad AFR exome AF: 0.209

Gnomad AMR exome AF: 0.473

Gnomad ASJ exome AF: 0.349

Gnomad EAS exome AF: 0.203

Gnomad FIN exome AF: 0.328

Gnomad NFE exome AF: 0.419

Gnomad OTH exome AF: 0.407

GnomAD4 exome AF: 0.413 AC: 448993 AN: 1087236 Hom.: 63430 Cov.: 29 AF XY: 0.416 AC XY: 148073 AN XY: 355964

African (AFR) AF: 0.201 AC: 5186 AN: 25784

American (AMR) AF: 0.479 AC: 15783 AN: 32916

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 6797 AN: 18983

East Asian (EAS) AF: 0.230 AC: 6940 AN: 30120

South Asian (SAS) AF: 0.437 AC: 22554 AN: 51664

European-Finnish (FIN) AF: 0.340 AC: 13714 AN: 40375

Middle Eastern (MID) AF: 0.412 AC: 1636 AN: 3971

European-Non Finnish (NFE) AF: 0.428 AC: 358732 AN: 837801

Other (OTH) AF: 0.387 AC: 17651 AN: 45622

GnomAD4 genome AF: 0.350 AC: 38999 AN: 111294 Hom.: 5311 Cov.: 23 AF XY: 0.342 AC XY: 11477 AN XY: 33512

African (AFR) AF: 0.206 AC: 6354 AN: 30771

American (AMR) AF: 0.438 AC: 4576 AN: 10445

Ashkenazi Jewish (ASJ) AF: 0.355 AC: 935 AN: 2636

East Asian (EAS) AF: 0.216 AC: 762 AN: 3526

South Asian (SAS) AF: 0.426 AC: 1141 AN: 2677

European-Finnish (FIN) AF: 0.317 AC: 1871 AN: 5905

Middle Eastern (MID) AF: 0.419 AC: 90 AN: 215

European-Non Finnish (NFE) AF: 0.423 AC: 22397 AN: 52929

Other (OTH) AF: 0.377 AC: 575 AN: 1524

Alfa AF: 0.391 Hom.: 5420

Bravo AF: 0.350

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypothyroidism, congenital, nongoitrous, 8 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0060
DANN	Benign	0.21
PhyloP100		-1.4
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: rs2239411; hg19: chrX-9665368; COSMIC: COSV54281086;