chrX-16841722-C-T

Variant names:

• chrX-16841722-C-T
• rs745481556
• NM_018360.3:c.1543C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_018360.3(TXLNG):​c.1543C>T​(p.Pro515Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,209,988 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 22 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000043 (0 hom. 22 hem.)
• Consequence: TXLNG NM_018360.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47
• Publications: 0 publications found

Genes affected

TXLNG (HGNC:18578): (taxilin gamma) This gene encodes a member of the taxilin family. The encoded protein binds to the C-terminal coiled-coil region of syntaxin family members 1A, 3A and 4A, and may play a role in intracellular vesicle trafficking. This gene is up-regulated by lipopolysaccharide and the gene product may be involved in cell cycle regulation. The related mouse protein was also shown to inhibit activating transcription factor 4-mediated transcription and thus regulate bone mass accrual. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2009]

RBBP7 (HGNC:9890): (RB binding protein 7, chromatin remodeling factor) This protein is a ubiquitously expressed nuclear protein and belongs to a highly conserved subfamily of WD-repeat proteins. It is found among several proteins that binds directly to retinoblastoma protein, which regulates cell proliferation. The encoded protein is found in many histone deacetylase complexes, including mSin3 co-repressor complex. It is also present in protein complexes involved in chromatin assembly. This protein can interact with BRCA1 tumor-suppressor gene and may have a role in the regulation of cell proliferation and differentiation. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

RBBP7 Gene-Disease associations (from GenCC):

• spermatogenic failure, X-linked, 9

  Inheritance: XL Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.063714564).
• BS2: High Hemizygotes in GnomAdExome4 at 22 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXLNG	NM_018360.3	c.1543C>T	p.Pro515Ser	missense_variant	Exon 10 of 10	ENST00000380122.10	NP_060830.2
TXLNG	NM_001168683.2	c.1147C>T	p.Pro383Ser	missense_variant	Exon 8 of 8		NP_001162154.1
TXLNG	XM_024452400.2	c.1426C>T	p.Pro476Ser	missense_variant	Exon 10 of 10		XP_024308168.1
TXLNG	XM_017029631.2	c.928C>T	p.Pro310Ser	missense_variant	Exon 7 of 7		XP_016885120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXLNG	ENST00000380122.10	c.1543C>T	p.Pro515Ser	missense_variant	Exon 10 of 10	1	NM_018360.3	ENSP00000369465.5
TXLNG	ENST00000398155.4	c.1147C>T	p.Pro383Ser	missense_variant	Exon 8 of 8	1		ENSP00000381222.4
TXLNG	ENST00000485153.1	n.434C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
RBBP7	ENST00000425696.5	c.*8-2332G>A		intron_variant	Intron 4 of 4	5		ENSP00000415747.1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112019 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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 182503 AF XY: 0.0000149

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000369

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000428 AC: 47 AN: 1097969 Hom.: 0 Cov.: 32 AF XY: 0.0000606 AC XY: 22 AN XY: 363333

African (AFR) AF: 0.00 AC: 0 AN: 26393

American (AMR) AF: 0.00 AC: 0 AN: 35176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19353

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54080

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40531

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000558 AC: 47 AN: 842022

Other (OTH) AF: 0.00 AC: 0 AN: 46077

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112019 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34183

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30786

American (AMR) AF: 0.00 AC: 0 AN: 10617

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3595

South Asian (SAS) AF: 0.00 AC: 0 AN: 2717

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53194

Other (OTH) AF: 0.00 AC: 0 AN: 1495

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.029673), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1543C>T (p.P515S) alteration is located in exon 10 (coding exon 10) of the TXLNG gene. This alteration results from a C to T substitution at nucleotide position 1543, causing the proline (P) at amino acid position 515 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	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.56
DANN	Benign	0.70
DEOGEN2	Benign	0.075	T;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.58	T;T
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.064	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.
PhyloP100		1.5
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.050
Sift	Benign	0.22	T;T
Sift4G	Benign	0.079	T;T
Polyphen		0.0090	B;B
Vest4		0.044
MutPred		0.24		Loss of catalytic residue at P515 (P = 1e-04);.;
MVP		0.10
MPC		0.0071
ClinPred		0.052	T
GERP RS		2.7
Varity_R		0.033
gMVP		0.072
Mutation Taster		=92/8	polymorphism

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: rs745481556; hg19: chrX-16859845;