rs786205699

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The ENST00000585474.5(TXNL4A):c.-60-10936_-60-10903delACATGCCGTCAGCACGCACGGCGCTAGCGCGCGC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 414,754 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

TXNL4A
ENST00000585474.5 intron

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3O:1

Conservation

PhyloP100: 0.289

Publications

1 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: Likely_pathogenic. The variant received 8 ACMG points.

PP5

Variant 18-79988603-CGCGCGCGCTAGCGCCGTGCGTGCTGACGGCATGT-C is Pathogenic according to our data. Variant chr18-79988603-CGCGCGCGCTAGCGCCGTGCGTGCTGACGGCATGT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 190413.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TXNL4A	NM_006701.5 link	c.-245_-212delACATGCCGTCAGCACGCACGGCGCTAGCGCGCGC		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.-245_-212delACATGCCGTCAGCACGCACGGCGCTAGCGCGCGC		upstream_gene_variant		1	NM_006701.5	ENSP00000269601.4		P83876

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

150720

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000972

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000664

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000208

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000125

AC:

AN:

264034

Hom.:

AF XY:

0.000128

AC XY:

AN XY:

133246

show subpopulations

African (AFR)

AF:

0.000301

AC:

AN:

6644

American (AMR)

AF:

0.000334

AC:

AN:

5994

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7516

East Asian (EAS)

AF:

0.000209

AC:

AN:

19104

South Asian (SAS)

AF:

0.000193

AC:

AN:

5172

European-Finnish (FIN)

AF:

0.00

AC:

AN:

19282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

1162

European-Non Finnish (NFE)

AF:

0.000131

AC:

AN:

183834

Other (OTH)

AF:

0.00

AC:

AN:

15326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

AF:

0.000133

AC:

AN:

150720

Hom.:

Cov.:

AF XY:

0.0000815

AC XY:

AN XY:

73616

show subpopulations

African (AFR)

AF:

0.0000972

AC:

AN:

41152

American (AMR)

AF:

0.0000664

AC:

AN:

15062

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3330

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

67332

Other (OTH)

AF:

0.00

AC:

AN:

2070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000843

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 02, 2014

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

TXNL4A-related disorder

Pathogenic:1

Dec 22, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TXNL4A c.-245_-212del34 variant is located in the 5' untranslated region. This deletion, referred to as the type 2 promoter deletion, has been reported in the homozygous state in multiple unrelated individuals with Burn-McKeown syndrome (Wieczorek et al. 2014. PubMed ID: 25434003; Goos et al. 2017. PubMed ID: 28905882; Narayanan et al. 2020. PubMed ID: 32187816). Functional studies found this variants reduces the activity of the putative TXNL4A promoter (Wieczorek et al. 2014. PubMed ID: 25434003). This variant is reported in 0.064% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/18-77748603-CGCGCGCGCTAGCGCCGTGCGTGCTGACGGCATGT-C). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.29

Mutation Taster

=17/83

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