3-3129041-A-G

Variant names:

• chr3-3129041-A-G
• rs779568831
• NM_182916.3:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_182916.3(TRNT1):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRNT1 NM_182916.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.62
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• retinitis pigmentosa and erythrocytic microcytosis

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 3 pathogenic variants. Next in-frame start position is after 30 codons. Genomic position: 3129128. Lost 0.067 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNT1	NM_182916.3	c.1A>G	p.Met1?	start_lost	Exon 2 of 8	ENST00000251607.11	NP_886552.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11	c.1A>G	p.Met1?	start_lost	Exon 2 of 8	1	NM_182916.3	ENSP00000251607.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000807 AC: 2 AN: 247682 AF XY: 0.0000149

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000891

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1453844 Hom.: 0 Cov.: 29 AF XY: 0.00000415 AC XY: 3 AN XY: 722846

African (AFR) AF: 0.00 AC: 0 AN: 33324

American (AMR) AF: 0.00 AC: 0 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25752

East Asian (EAS) AF: 0.00 AC: 0 AN: 39620

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85428

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53164

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5712

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1107278

Other (OTH) AF: 0.00 AC: 0 AN: 60002

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Oct 14, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the TRNT1 mRNA. The next in-frame methionine is located at codon 30. This variant is present in population databases (rs779568831, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with TRNT1-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T;.;.;.;.;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	.;.;D;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Uncertain	0.54	D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
PhyloP100		2.6
PROVEAN	Benign	-0.53	N;D;N;D;D;N
REVEL	Uncertain	0.40
Sift	Pathogenic	0.0	D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D
Polyphen		0.71	P;.;P;.;.;.
Vest4		0.74
MVP		0.17
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.67
Mutation Taster		=27/173	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs779568831; hg19: chr3-3170725;