rs75033443

Positions:

• chr3-3129173-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_182916.3(TRNT1):​c.133C>T​(p.Leu45=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.014 in 1,613,990 control chromosomes in the GnomAD database, including 410 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (149 hom., cov: 34)
  • Exomes 𝑓: 0.012 (261 hom.)
• Consequence: TRNT1 NM_182916.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.508

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 3-3129173-C-T is Benign according to our data. Variant chr3-3129173-C-T is described in ClinVar as [Benign]. Clinvar id is 380598.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.508 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0827 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRNT1	NM_182916.3	c.133C>T	p.Leu45=	synonymous_variant	2/8	ENST00000251607.11	NP_886552.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11	c.133C>T	p.Leu45=	synonymous_variant	2/8	1	NM_182916.3	ENSP00000251607	P1

Frequencies

GnomAD3 genomes AF: 0.0307 AC: 4677 AN: 152184 Hom.: 147 Cov.: 34

Gnomad AFR AF: 0.0847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0229

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.000661

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.0311

GnomAD3 exomes AF: 0.0125 AC: 3152 AN: 251428 Hom.: 67 AF XY: 0.0107 AC XY: 1454 AN XY: 135908

Gnomad AFR exome AF: 0.0915

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00913

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00120

Gnomad NFE exome AF: 0.00968

Gnomad OTH exome AF: 0.00977

GnomAD4 exome AF: 0.0123 AC: 17934 AN: 1461688 Hom.: 261 Cov.: 35 AF XY: 0.0118 AC XY: 8567 AN XY: 727144

Gnomad4 AFR exome AF: 0.0871

Gnomad4 AMR exome AF: 0.0121

Gnomad4 ASJ exome AF: 0.00930

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000441

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.0118

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0309 AC: 4702 AN: 152302 Hom.: 149 Cov.: 34 AF XY: 0.0289 AC XY: 2149 AN XY: 74470

Gnomad4 AFR AF: 0.0850

Gnomad4 AMR AF: 0.0229

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.000661

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.0307

Alfa AF: 0.0225 Hom.: 39

Bravo AF: 0.0350

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.0102

EpiControl AF: 0.0115

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 22, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 17, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.0
DANN	Benign	0.88

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: rs75033443; hg19: chr3-3170857;