3-3144641-AAGTT-A

Position:

chr3-3144641-AAGTT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_182916.3(TRNT1):c.542_545delTTAG(p.Val181fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000303 in 1,586,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

TRNT1
NM_182916.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 7.84

Variant links:

Genes affected

TRNT1 (HGNC:17341): (tRNA nucleotidyl transferase 1) The protein encoded by this gene is a CCA-adding enzyme which belongs to the tRNA nucleotidyltransferase/poly(A) polymerase family. This essential enzyme functions by catalyzing the addition of the conserved nucleotide triplet CCA to the 3' terminus of tRNA molecules. Mutations in this gene result in sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

TRNT1 links:

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

CRBN links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-3144641-AAGTT-A is Pathogenic according to our data. Variant chr3-3144641-AAGTT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 423189.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-3144641-AAGTT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNT1	NM_182916.3 linkuse as main transcript	c.542_545delTTAG	p.Val181fs	frameshift_variant	5/8	ENST00000251607.11	NP_886552.3	Q96Q11-1A0A024R2H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11 linkuse as main transcript	c.542_545delTTAG	p.Val181fs	frameshift_variant	5/8	1	NM_182916.3	ENSP00000251607.6		Q96Q11-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000812

AC:

AN:

246268

Hom.:

AF XY:

0.00000750

AC XY:

AN XY:

133252

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000293

AC:

AN:

1434062

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

713754

show subpopulations

Gnomad4 AFR exome

AF:

0.0000306

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000357

Gnomad4 OTH exome

AF:

0.0000339

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Retinal dystrophy

Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Dept Of Ophthalmology, Nagoya University	Oct 01, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	Jan 01, 2019	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 02, 2024

The c.542_545delTTAG (p.V181Dfs*18) alteration, located in exon 5 (coding exon 4) of the TRNT1 gene, consists of a deletion of 4 nucleotides from position 542 to 545, causing a translational frameshift with a predicted alternate stop codon after 18 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.542_545delTTAG allele has an overall frequency of 0.001% (2/246268) total alleles studied. The highest observed frequency was 0.002% (2/112514) of European (non-Finnish) alleles. Based on the available evidence, this alteration is classified as pathogenic. -

TRNT1-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The TRNT1 c.542_545delTTAG variant is predicted to result in a frameshift and premature protein termination (p.Val181Aspfs*18). To our knowledge, this variant has not been reported in the literature in individuals with TRNT1-related disorders. However, this variant was reported in the heterozygous state in a study of individuals who volunteered for whole genome sequencing (Dataset 1, Tab 3, Hou et al. 2020. PubMed ID: 31980526). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-3186325-AAGTT-A). Frameshift variants in TRNT1 are expected to be pathogenic. This variant is interpreted as likely pathogenic. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 27, 2017

The c.542_545delTTAG variant in the TRNT1 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.542_545delTTAG variant causes a frameshift starting with codon Valine 181, changes this amino acid to a Aspartic acid residue, and creates a premature Stop codon at position 18 of the new reading frame, denoted p.Val181AspfsX18. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.542_545delTTAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.542_545delTTAG as a strong candidate for a likely pathogenic variant; however, the possibility it may be a rare benign variant cannot be excluded. -

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 01, 2023

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Val181Aspfs*18) in the TRNT1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TRNT1 are known to be pathogenic (PMID: 25193871). This variant is present in population databases (rs769317780, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with TRNT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 423189). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over