rs334773

chr3-3129108-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_182916.3(TRNT1):c.68C>T(p.Pro23Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.983 in 1,614,056 control chromosomes in the GnomAD database, including 783,687 homozygotes. 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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P23A) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.92 (64988 hom., cov: 32)
  • Exomes 𝑓: 0.99 (718699 hom.)
• Consequence: TRNT1 NM_182916.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.876

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5487294E-7).
• BP6: Variant 3-3129108-C-T is Benign according to our data. Variant chr3-3129108-C-T is described in ClinVar as [Benign]. Clinvar id is 403570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRNT1	NM_182916.3	c.68C>T	p.Pro23Leu	missense_variant	2/8	ENST00000251607.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRNT1	ENST00000251607.11	c.68C>T	p.Pro23Leu	missense_variant	2/8	1	NM_182916.3	P1

Frequencies

GnomAD3 genomes AF: 0.915 AC: 139197 AN: 152090 Hom.: 64946 Cov.: 32

Gnomad AFR AF: 0.709

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.963

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.968

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.941

GnomAD3 exomes AF: 0.977 AC: 245656 AN: 251472 Hom.: 120711 AF XY: 0.983 AC XY: 133652 AN XY: 135912

Gnomad AFR exome AF: 0.698

Gnomad AMR exome AF: 0.982

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.988

GnomAD4 exome AF: 0.990 AC: 1447952 AN: 1461848 Hom.: 718699 Cov.: 43 AF XY: 0.992 AC XY: 721280 AN XY: 727230

Gnomad4 AFR exome AF: 0.694

Gnomad4 AMR exome AF: 0.979

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.999

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 0.999

Gnomad4 OTH exome AF: 0.979

GnomAD4 genome AF: 0.915 AC: 139300 AN: 152208 Hom.: 64988 Cov.: 32 AF XY: 0.919 AC XY: 68381 AN XY: 74434

Gnomad4 AFR AF: 0.709

Gnomad4 AMR AF: 0.963

Gnomad4 ASJ AF: 0.999

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.999

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.998

Gnomad4 OTH AF: 0.941

Alfa AF: 0.984 Hom.: 150573

Bravo AF: 0.901

TwinsUK AF: 0.999 AC: 3703

ALSPAC AF: 0.999 AC: 3849

ESP6500AA AF: 0.713 AC: 3142

ESP6500EA AF: 0.998 AC: 8587

ExAC AF: 0.972 AC: 118037

Asia WGS AF: 0.983 AC: 3418 AN: 3478

EpiCase AF: 0.998

EpiControl AF: 0.997

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified Benign:2

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 -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 100% of patients studied by a panel of primary immunodeficiencies. Number of patients: 95. Only high quality variants are reported. -

Retinitis pigmentosa and erythrocytic microcytosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	14
Dann	Benign	0.83
DEOGEN2	Benign	0.033	T;.;.;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.11	N
MetaRNN	Benign	5.5e-7	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.4	N;N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.33	N;N;N;N;N;N
REVEL	Benign	0.034
Sift	Benign	0.73	T;T;T;T;T;T
Sift4G	Benign	0.86	T;T;T;T;T;T
Polyphen		0.0	B;.;B;.;.;.
Vest4		0.082
MPC		0.0049
ClinPred		0.0026	T
GERP RS		3.4
Varity_R		0.025
gMVP		0.28

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: rs334773; hg19: chr3-3170792;