X-16841740-G-C

Position:

• chrX-16841740-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018360.3(TXLNG):​c.1561G>C​(p.Ala521Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000456 in 1,096,889 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000046 (0 hom. 1 hem.)
• Consequence: TXLNG NM_018360.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051268905).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TXLNG	NM_018360.3	c.1561G>C	p.Ala521Pro	missense_variant	10/10	ENST00000380122.10	NP_060830.2
TXLNG	NM_001168683.2	c.1165G>C	p.Ala389Pro	missense_variant	8/8		NP_001162154.1
TXLNG	XM_024452400.2	c.1444G>C	p.Ala482Pro	missense_variant	10/10		XP_024308168.1
TXLNG	XM_017029631.2	c.946G>C	p.Ala316Pro	missense_variant	7/7		XP_016885120.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TXLNG	ENST00000380122.10	c.1561G>C	p.Ala521Pro	missense_variant	10/10	1	NM_018360.3	ENSP00000369465.5
TXLNG	ENST00000398155.4	c.1165G>C	p.Ala389Pro	missense_variant	8/8	1		ENSP00000381222.4
RBBP7	ENST00000425696.5	c.*8-2350C>G		intron_variant		5		ENSP00000415747.1
TXLNG	ENST00000485153.1	n.452G>C		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000221 AC: 4 AN: 180692 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 65490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000291

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000456 AC: 5 AN: 1096889 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362359

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000166

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 06, 2023

The c.1561G>C (p.A521P) alteration is located in exon 10 (coding exon 10) of the TXLNG gene. This alteration results from a G to C substitution at nucleotide position 1561, causing the alanine (A) at amino acid position 521 to be replaced by a proline (P). 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	0.072
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	10
DANN	Benign	0.97
DEOGEN2	Benign	0.025	T;.
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.56	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.051	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.40	N;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.43	N;N
REVEL	Benign	0.044
Sift	Benign	0.13	T;T
Sift4G	Benign	0.28	T;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.13		Gain of glycosylation at A521 (P = 0.025);.;
MVP		0.22
MPC		0.0066
ClinPred		0.025	T
GERP RS		1.9
Varity_R		0.10
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs761862450; hg19: chrX-16859863;