3-3140611-G-T

Variant names:

• chr3-3140611-G-T
• rs41399044
• NM_182916.3:c.444G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182916.3(TRNT1):​c.444G>T​(p.Ala148Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0178 in 1,613,944 control chromosomes in the GnomAD database, including 609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A148A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.040 (242 hom., cov: 34)
  • Exomes 𝑓: 0.016 (367 hom.)
• Consequence: TRNT1 NM_182916.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.578
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 3-3140611-G-T is Benign according to our data. Variant chr3-3140611-G-T is described in ClinVar as Benign. ClinVar VariationId is 380599.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.578 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.106 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.444G>T	p.Ala148Ala	synonymous	Exon 4 of 8	NP_886552.3	Q96Q11-1
	TRNT1	NM_001367321.1		c.444G>T	p.Ala148Ala	synonymous	Exon 4 of 9	NP_001354250.1	Q96Q11-1
	TRNT1	NM_001367322.1		c.444G>T	p.Ala148Ala	synonymous	Exon 4 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.444G>T	p.Ala148Ala	synonymous	Exon 4 of 8	ENSP00000251607.6	Q96Q11-1
	TRNT1	ENST00000280591.10	TSL:1	c.444G>T	p.Ala148Ala	synonymous	Exon 4 of 8	ENSP00000280591.6	Q96Q11-2
	TRNT1	ENST00000698413.1		c.561G>T	p.Ala187Ala	synonymous	Exon 6 of 10	ENSP00000513706.1	A0A8V8TM71

Frequencies

GnomAD3 genomes AF: 0.0393 AC: 5986 AN: 152134 Hom.: 239 Cov.: 34

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0291

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0411

GnomAD2 exomes AF: 0.0162 AC: 4063 AN: 251422 AF XY: 0.0140

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.00933

Gnomad EAS exome AF: 0.00288

Gnomad FIN exome AF: 0.00125

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0155 AC: 22698 AN: 1461692 Hom.: 367 Cov.: 31 AF XY: 0.0150 AC XY: 10884 AN XY: 727156

African (AFR) AF: 0.109 AC: 3658 AN: 33462

American (AMR) AF: 0.0142 AC: 636 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00953 AC: 249 AN: 26132

East Asian (EAS) AF: 0.00154 AC: 61 AN: 39678

South Asian (SAS) AF: 0.00347 AC: 299 AN: 86244

European-Finnish (FIN) AF: 0.00210 AC: 112 AN: 53410

Middle Eastern (MID) AF: 0.0137 AC: 79 AN: 5768

European-Non Finnish (NFE) AF: 0.0148 AC: 16443 AN: 1111898

Other (OTH) AF: 0.0192 AC: 1161 AN: 60380

GnomAD4 genome AF: 0.0395 AC: 6015 AN: 152252 Hom.: 242 Cov.: 34 AF XY: 0.0372 AC XY: 2769 AN XY: 74434

African (AFR) AF: 0.108 AC: 4491 AN: 41528

American (AMR) AF: 0.0290 AC: 444 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00367 AC: 19 AN: 5184

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4822

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10602

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0133 AC: 906 AN: 68026

Other (OTH) AF: 0.0412 AC: 87 AN: 2114

Alfa AF: 0.0222 Hom.: 61

Bravo AF: 0.0448

Asia WGS AF: 0.0220 AC: 75 AN: 3478

EpiCase AF: 0.0136

EpiControl AF: 0.0136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (1)
-	-	1	not provided (1)
-	-	1	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	6.0
DANN	Benign	0.62
PhyloP100		-0.58
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs41399044; hg19: chr3-3182295;