NM_018360.3:c.1527A>C

Variant names:

• chrX-16841706-A-C
• rs34744750
• NM_018360.3:c.1527A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018360.3(TXLNG):​c.1527A>C​(p.Arg509Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,210,181 control chromosomes in the GnomAD database, including 20 homozygotes. There are 508 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (7 hom., 255 hem., cov: 22)
  • Exomes 𝑓: 0.00093 (13 hom. 253 hem.)
• Consequence: TXLNG NM_018360.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.131
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029144883).
• BP6: Variant X-16841706-A-C is Benign according to our data. Variant chrX-16841706-A-C is described in ClinVar as [Benign]. Clinvar id is 714920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00857 (960/111971) while in subpopulation AFR AF = 0.0296 (911/30797). AF 95% confidence interval is 0.028. There are 7 homozygotes in GnomAd4. There are 255 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXLNG	NM_018360.3	c.1527A>C	p.Arg509Ser	missense_variant	Exon 10 of 10	ENST00000380122.10	NP_060830.2
TXLNG	NM_001168683.2	c.1131A>C	p.Arg377Ser	missense_variant	Exon 8 of 8		NP_001162154.1
TXLNG	XM_024452400.2	c.1410A>C	p.Arg470Ser	missense_variant	Exon 10 of 10		XP_024308168.1
TXLNG	XM_017029631.2	c.912A>C	p.Arg304Ser	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.1527A>C	p.Arg509Ser	missense_variant	Exon 10 of 10	1	NM_018360.3	ENSP00000369465.5
TXLNG	ENST00000398155.4	c.1131A>C	p.Arg377Ser	missense_variant	Exon 8 of 8	1		ENSP00000381222.4
TXLNG	ENST00000485153.1	n.418A>C		non_coding_transcript_exon_variant	Exon 2 of 2	3
RBBP7	ENST00000425696.5	c.*8-2316T>G		intron_variant	Intron 4 of 4	5		ENSP00000415747.1

Frequencies

GnomAD3 genomes AF: 0.00856 AC: 958 AN: 111918 Hom.: 7 Cov.: 22

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00312

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: 0.0000940

Gnomad OTH AF: 0.00735

GnomAD2 exomes AF: 0.00271 AC: 496 AN: 183038 AF XY: 0.00154

Gnomad AFR exome AF: 0.0335

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00177

GnomAD4 exome AF: 0.000930 AC: 1021 AN: 1098210 Hom.: 13 Cov.: 32 AF XY: 0.000696 AC XY: 253 AN XY: 363568

African (AFR) AF: 0.0321 AC: 848 AN: 26402

American (AMR) AF: 0.00179 AC: 63 AN: 35199

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19379

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54136

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40533

Middle Eastern (MID) AF: 0.00121 AC: 5 AN: 4134

European-Non Finnish (NFE) AF: 0.0000142 AC: 12 AN: 842127

Other (OTH) AF: 0.00193 AC: 89 AN: 46094

GnomAD4 genome AF: 0.00857 AC: 960 AN: 111971 Hom.: 7 Cov.: 22 AF XY: 0.00746 AC XY: 255 AN XY: 34171

African (AFR) AF: 0.0296 AC: 911 AN: 30797

American (AMR) AF: 0.00311 AC: 33 AN: 10601

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3584

South Asian (SAS) AF: 0.00 AC: 0 AN: 2686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6077

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

European-Non Finnish (NFE) AF: 0.0000941 AC: 5 AN: 53160

Other (OTH) AF: 0.00726 AC: 11 AN: 1516

Alfa AF: 0.00344 Hom.: 146

Bravo AF: 0.0104

ESP6500AA AF: 0.0362 AC: 139

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00292 AC: 355

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.96
DANN	Benign	0.44
DEOGEN2	Benign	0.029	T;.
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.49	T;T
MetaRNN	Benign	0.0029	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;.
PhyloP100		-0.13
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.63	N;N
REVEL	Benign	0.036
Sift	Benign	0.74	T;T
Sift4G	Benign	0.67	T;T
Polyphen		0.0	B;B
Vest4		0.084
MutPred		0.20		Gain of phosphorylation at R509 (P = 0.022);.;
MVP		0.068
MPC		0.0068
ClinPred		0.00077	T
GERP RS		-2.8
Varity_R		0.23
gMVP		0.13
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: rs34744750; hg19: chrX-16859829;