X-9653621-G-C

Variant names:

• chrX-9653621-G-C
• rs1434127508
• NM_005647.4:c.35G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005647.4(TBL1X):​c.35G>C​(p.Cys12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000944 in 1,059,073 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.4e-7 (0 hom. 0 hem.)
• Consequence: TBL1X NM_005647.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.248

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07359624).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TBL1X	NM_005647.4	c.35G>C	p.Cys12Ser	missense_variant	Exon 4 of 18	ENST00000645353.2	NP_005638.1
TBL1X	NM_001139466.1	c.35G>C	p.Cys12Ser	missense_variant	Exon 4 of 18		NP_001132938.1
TBL1X	NM_001139467.1	c.-50-594G>C		intron_variant	Intron 3 of 16		NP_001132939.1
TBL1X	NM_001139468.1	c.-50-594G>C		intron_variant	Intron 4 of 17		NP_001132940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TBL1X	ENST00000645353.2	c.35G>C	p.Cys12Ser	missense_variant	Exon 4 of 18		NM_005647.4	ENSP00000496215.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.44e-7 AC: 1 AN: 1059073 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 346009

African (AFR) AF: 0.00 AC: 0 AN: 25134

American (AMR) AF: 0.00 AC: 0 AN: 29044

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18687

East Asian (EAS) AF: 0.00 AC: 0 AN: 27374

South Asian (SAS) AF: 0.00 AC: 0 AN: 50013

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4104

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 822183

Other (OTH) AF: 0.00 AC: 0 AN: 44594

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 23, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.35G>C (p.C12S) alteration is located in exon 4 (coding exon 1) of the TBL1X gene. This alteration results from a G to C substitution at nucleotide position 35, causing the cysteine (C) at amino acid position 12 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.2
DANN	Benign	0.62
DEOGEN2	Benign	0.19	T;T;T;T;T;T;T
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.44	T;T;.;.;.;.;T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.074	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.;N;N;N;N;.
PhyloP100		-0.25
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.070	N;D;N;.;.;.;N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D;D;D;.;.;.;D
Sift4G	Pathogenic	0.0	D;D;D;.;.;.;D
Polyphen		0.0	B;.;B;B;B;B;.
Vest4		0.19
MutPred		0.34		Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);Gain of phosphorylation at C12 (P = 0.0238);
MVP		0.15
MPC		1.0
ClinPred		0.042	T
GERP RS		-1.8
Varity_R		0.35
gMVP		0.33
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Other links and lift over

dbSNP: rs1434127508; hg19: chrX-9621661;