rs334773

Variant names:

• chr3-3129108-C-T
• rs334773
• NM_182916.3:c.68C>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in 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:8
• Conservation: PhyloP100: 0.876
• Publications: 31 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: Laboratory for Molecular Medicine, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa and erythrocytic microcytosis

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182916.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRNT1	NM_182916.3	MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 2 of 8	NP_886552.3	Q96Q11-1
	TRNT1	NM_001367321.1		c.68C>T	p.Pro23Leu	missense	Exon 2 of 9	NP_001354250.1	Q96Q11-1
	TRNT1	NM_001367322.1		c.68C>T	p.Pro23Leu	missense	Exon 2 of 8	NP_001354251.1	Q96Q11-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRNT1	ENST00000251607.11	TSL:1 MANE Select	c.68C>T	p.Pro23Leu	missense	Exon 2 of 8	ENSP00000251607.6	Q96Q11-1
	TRNT1	ENST00000280591.10	TSL:1	c.68C>T	p.Pro23Leu	missense	Exon 2 of 8	ENSP00000280591.6	Q96Q11-2
	TRNT1	ENST00000339437.11	TSL:1	c.68C>T	p.Pro23Leu	missense	Exon 2 of 3	ENSP00000342985.6	Q96Q11-3

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

GnomAD2 exomes AF: 0.977 AC: 245656 AN: 251472 AF XY: 0.983

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 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

African (AFR) AF: 0.694 AC: 23221 AN: 33470

American (AMR) AF: 0.979 AC: 43775 AN: 44722

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26126 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39698 AN: 39698

South Asian (SAS) AF: 0.999 AC: 86194 AN: 86254

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53418

Middle Eastern (MID) AF: 0.980 AC: 5651 AN: 5766

European-Non Finnish (NFE) AF: 0.999 AC: 1110720 AN: 1111988

Other (OTH) AF: 0.979 AC: 59149 AN: 60396

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

African (AFR) AF: 0.709 AC: 29387 AN: 41452

American (AMR) AF: 0.963 AC: 14737 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3469 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 0.999 AC: 4826 AN: 4830

European-Finnish (FIN) AF: 1.00 AC: 10609 AN: 10610

Middle Eastern (MID) AF: 0.976 AC: 287 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67903 AN: 68038

Other (OTH) AF: 0.941 AC: 1984 AN: 2108

Alfa AF: 0.978 Hom.: 198879

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (3)
-	-	3	not specified (3)
-	-	1	not provided (1)
-	-	1	Retinitis pigmentosa and erythrocytic microcytosis (1)

Computational scores

Source: dbNSFP v4.9

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
LIST_S2	Benign	0.14	T
MetaRNN	Benign	5.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.4	N
PhyloP100		0.88
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.33	N
REVEL	Benign	0.034
Sift	Benign	0.73	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.082
MPC		0.0049
ClinPred		0.0026	T
GERP RS		3.4
Varity_R		0.025
gMVP		0.28
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs334773; hg19: chr3-3170792; COSMIC: COSV107243524; COSMIC: COSV107243524;