3-3140628-C-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_182916.3(TRNT1):c.461C>T(p.Thr154Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T154P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TRNT1
NM_182916.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.73

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Laboratory for Molecular Medicine
retinitis pigmentosa and erythrocytic microcytosis
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

TRNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.991

PP5

Variant 3-3140628-C-T is Pathogenic according to our data. Variant chr3-3140628-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 157617.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRNT1	NM_182916.3	MANE Select	c.461C>T	p.Thr154Ile	missense	Exon 4 of 8	NP_886552.3	Q96Q11-1
TRNT1	NM_001367321.1		c.461C>T	p.Thr154Ile	missense	Exon 4 of 9	NP_001354250.1	Q96Q11-1
TRNT1	NM_001367322.1		c.461C>T	p.Thr154Ile	missense	Exon 4 of 8	NP_001354251.1	Q96Q11-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRNT1	ENST00000251607.11	TSL:1 MANE Select	c.461C>T	p.Thr154Ile	missense	Exon 4 of 8	ENSP00000251607.6	Q96Q11-1
TRNT1	ENST00000280591.10	TSL:1	c.461C>T	p.Thr154Ile	missense	Exon 4 of 8	ENSP00000280591.6	Q96Q11-2
TRNT1	ENST00000698413.1		c.578C>T	p.Thr193Ile	missense	Exon 6 of 10	ENSP00000513706.1	A0A8V8TM71

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152208

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461660

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111940

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68046

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.88

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.9

PhyloP100

7.7

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.96

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

1.0

MutPred

0.89

Gain of glycosylation at T154 (P = 0.032)

MVP

1.0

MPC

0.022

ClinPred

1.0

GERP RS

5.7

Varity_R

0.96

gMVP

0.98

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over