chrX-16841458-C-G

Variant names:

• chrX-16841458-C-G
• rs142922936
• NM_018360.3:c.1279C>G

Variant summary

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

The NM_018360.3(TXLNG):​c.1279C>G​(p.Leu427Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000434 in 1,209,178 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 187 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.00046 (0 hom. 179 hem.)
• Consequence: TXLNG NM_018360.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.47
• Publications: 2 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=0.06757125).
• BS2: High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXLNG	NM_018360.3	c.1279C>G	p.Leu427Val	missense_variant	Exon 10 of 10	ENST00000380122.10	NP_060830.2
TXLNG	NM_001168683.2	c.883C>G	p.Leu295Val	missense_variant	Exon 8 of 8		NP_001162154.1
TXLNG	XM_024452400.2	c.1162C>G	p.Leu388Val	missense_variant	Exon 10 of 10		XP_024308168.1
TXLNG	XM_017029631.2	c.664C>G	p.Leu222Val	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.1279C>G	p.Leu427Val	missense_variant	Exon 10 of 10	1	NM_018360.3	ENSP00000369465.5
TXLNG	ENST00000398155.4	c.883C>G	p.Leu295Val	missense_variant	Exon 8 of 8	1		ENSP00000381222.4
TXLNG	ENST00000485153.1	n.170C>G		non_coding_transcript_exon_variant	Exon 2 of 2	3
RBBP7	ENST00000425696.5	c.*8-2068G>C		intron_variant	Intron 4 of 4	5		ENSP00000415747.1

Frequencies

GnomAD3 genomes AF: 0.000170 AC: 19 AN: 111644 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000653

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000952

Gnomad ASJ AF: 0.000755

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00833

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00134

GnomAD2 exomes AF: 0.000237 AC: 43 AN: 181596 AF XY: 0.000287

Gnomad AFR exome AF: 0.0000763

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.000547

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000431

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000463 AC: 508 AN: 1097484 Hom.: 0 Cov.: 30 AF XY: 0.000493 AC XY: 179 AN XY: 362958

African (AFR) AF: 0.00 AC: 0 AN: 26330

American (AMR) AF: 0.0000570 AC: 2 AN: 35089

Ashkenazi Jewish (ASJ) AF: 0.000672 AC: 13 AN: 19335

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30199

South Asian (SAS) AF: 0.000167 AC: 9 AN: 54042

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4132

European-Non Finnish (NFE) AF: 0.000533 AC: 449 AN: 841780

Other (OTH) AF: 0.000630 AC: 29 AN: 46050

GnomAD4 genome AF: 0.000152 AC: 17 AN: 111694 Hom.: 0 Cov.: 23 AF XY: 0.000236 AC XY: 8 AN XY: 33886

African (AFR) AF: 0.0000651 AC: 2 AN: 30717

American (AMR) AF: 0.0000951 AC: 1 AN: 10513

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 2 AN: 2650

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6009

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.000188 AC: 10 AN: 53157

Other (OTH) AF: 0.00132 AC: 2 AN: 1513

Alfa AF: 0.000521 Hom.: 3

Bravo AF: 0.000196

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000222 AC: 27

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1279C>G (p.L427V) alteration is located in exon 10 (coding exon 10) of the TXLNG gene. This alteration results from a C to G substitution at nucleotide position 1279, causing the leucine (L) at amino acid position 427 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.068	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M;.
PhyloP100		2.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.5	N;N
REVEL	Benign	0.089
Sift	Benign	0.060	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.49	P;B
Vest4		0.064
MVP		0.18
MPC		0.011
ClinPred		0.066	T
GERP RS		2.3
Varity_R		0.19
gMVP		0.45
Mutation Taster		=94/6	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: rs142922936; hg19: chrX-16859581;