rs535089924

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PP5_Very_StrongBS1_SupportingBS2

The ENST00000585474.5(TXNL4A):c.-60-10913_-60-10880delCTAGCGCGCGCGCATGCCGTCAGCACGCACGGCG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00418 in 516,266 control chromosomes in the GnomAD database, including 9 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0047 ( 3 hom., cov: 34)

Exomes 𝑓: 0.0040 ( 6 hom. )

Consequence

TXNL4A
ENST00000585474.5 intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

Conservation

PhyloP100: 0.206

Publications

0 publications found

Variant links:

Genes affected

TXNL4A (HGNC:30551): (thioredoxin like 4A) The protein encoded by this gene is a member of the U5 small ribonucleoprotein particle (snRNP), and is involved in pre-mRNA splicing. This protein contains a thioredoxin-like fold and it is expected to interact with multiple proteins. Protein-protein interactions have been observed with the polyglutamine tract-binding protein 1 (PQBP1). Mutations in both the coding region and promoter region of this gene have been associated with Burn-McKeown syndrome, which is a rare disorder characterized by craniofacial dysmorphisms, cardiac defects, hearing loss, and bilateral choanal atresia. A pseudogene of this gene is found on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2015]

TXNL4A Gene-Disease associations (from GenCC):

choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome
Inheritance: AR, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, G2P

TXNL4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP5

Variant 18-79988580-ACGCCGTGCGTGCTGACGGCATGCGCGCGCGCTAG-A is Pathogenic according to our data. Variant chr18-79988580-ACGCCGTGCGTGCTGACGGCATGCGCGCGCGCTAG-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00468 (710/151694) while in subpopulation AMR AF = 0.0074 (113/15278). AF 95% confidence interval is 0.00629. There are 3 homozygotes in GnomAd4. There are 354 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 3 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNL4A	NM_006701.5 link	c.-222_-189delCTAGCGCGCGCGCATGCCGTCAGCACGCACGGCG		upstream_gene_variant		ENST00000269601.10	NP_006692.1	P83876

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TXNL4A	ENST00000269601.10 link	c.-222_-189delCTAGCGCGCGCGCATGCCGTCAGCACGCACGGCG		upstream_gene_variant		1	NM_006701.5	ENSP00000269601.4		P83876

Frequencies

GnomAD3 genomes

AF:

0.00468

AC:

709

AN:

151586

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00321

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00741

Gnomad ASJ

AF:

0.0202

Gnomad EAS

AF:

0.00137

Gnomad SAS

AF:

0.00146

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00506

Gnomad OTH

AF:

0.00528

GnomAD4 exome

AF:

0.00397

AC:

1449

AN:

364572

Hom.:

AF XY:

0.00405

AC XY:

736

AN XY:

181734

show subpopulations

African (AFR)

AF:

0.00131

AC:

AN:

8386

American (AMR)

AF:

0.00431

AC:

AN:

6496

Ashkenazi Jewish (ASJ)

AF:

0.0159

AC:

139

AN:

8752

East Asian (EAS)

AF:

0.00107

AC:

AN:

20546

South Asian (SAS)

AF:

0.000763

AC:

AN:

7860

European-Finnish (FIN)

AF:

0.00166

AC:

AN:

20538

Middle Eastern (MID)

AF:

0.00698

AC:

AN:

1432

European-Non Finnish (NFE)

AF:

0.00404

AC:

1096

AN:

271322

Other (OTH)

AF:

0.00535

AC:

103

AN:

19240

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00468

AC:

710

AN:

151694

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

354

AN XY:

74186

show subpopulations

African (AFR)

AF:

0.00322

AC:

133

AN:

41250

American (AMR)

AF:

0.00740

AC:

113

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.0202

AC:

AN:

3466

East Asian (EAS)

AF:

0.00137

AC:

AN:

5104

South Asian (SAS)

AF:

0.00146

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.00142

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00506

AC:

344

AN:

67922

Other (OTH)

AF:

0.00523

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

122

153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00435

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome

Pathogenic:7Uncertain:1Other:1

Dec 18, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 27, 2019

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2021

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Oct 21, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TXNL4A c.-222_-189del34 is a deletion in the promoter region. 4/4 computational tools predict no significant impact on normal splicing. The variant allele was found at a frequency of 0.0036 in 31196 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in TXNL4A causing Choanal Atresia-Hearing Loss-Cardiac Defects-Craniofacial Dysmorphism Syndrome (0.0036 vs ND), allowing no conclusion about variant significance. c.-222_-189del34 has been reported in the literature in multiple individuals affected with Choanal Atresia-Hearing Loss-Cardiac Defects-Craniofacial Dysmorphism Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this deletion resulted in a decrease of TXNL4A expression to about 40% of wild type. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (pathogenic/likely pathogenic n=3, VUS n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 04, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Apr 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 23, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:2

Oct 28, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies suggest a damaging effect: reduced transcriptional activity (PMID: 25434003); This variant is associated with the following publications: (PMID: 32735620, 25434003, 34426522, 28905882) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TXNL4A: PM3:Very Strong, PM2:Supporting, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.21

Mutation Taster

=42/58

disease causing (ClinVar)

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over