3-3147595-A-G

Variant names:

• chr3-3147595-A-G
• rs1705805
• NM_182916.3:c.948A>G

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.948A>G​(p.Ala316Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.815 in 1,613,574 control chromosomes in the GnomAD database, including 541,540 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. A316A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.74 (43385 hom., cov: 31)
  • Exomes 𝑓: 0.82 (498155 hom.)
• Consequence: TRNT1 NM_182916.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.905
• 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]

CRBN (HGNC:30185): (cereblon) This gene encodes a protein related to the Lon protease protein family. In rodents and other mammals this gene product is found in the cytoplasm localized with a calcium channel membrane protein, and is thought to play a role in brain development. Mutations in this gene are associated with autosomal recessive nonsyndromic cognitive disability. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

CRBN Gene-Disease associations (from GenCC):

• intellectual disability

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• intellectual disability, autosomal recessive 2

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 3-3147595-A-G is Benign according to our data. Variant chr3-3147595-A-G is described in ClinVar as Benign. ClinVar VariationId is 380145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.905 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNT1	NM_182916.3	c.948A>G	p.Ala316Ala	synonymous_variant	Exon 7 of 8	ENST00000251607.11	NP_886552.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11	c.948A>G	p.Ala316Ala	synonymous_variant	Exon 7 of 8	1	NM_182916.3	ENSP00000251607.6

Frequencies

GnomAD3 genomes AF: 0.742 AC: 112629 AN: 151880 Hom.: 43370 Cov.: 31

Gnomad AFR AF: 0.514

Gnomad AMI AF: 0.899

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.866

Gnomad EAS AF: 0.939

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.799

Gnomad MID AF: 0.823

Gnomad NFE AF: 0.837

Gnomad OTH AF: 0.758

GnomAD2 exomes AF: 0.799 AC: 200214 AN: 250614 AF XY: 0.810

Gnomad AFR exome AF: 0.499

Gnomad AMR exome AF: 0.686

Gnomad ASJ exome AF: 0.862

Gnomad EAS exome AF: 0.941

Gnomad FIN exome AF: 0.798

Gnomad NFE exome AF: 0.841

Gnomad OTH exome AF: 0.820

GnomAD4 exome AF: 0.823 AC: 1202908 AN: 1461576 Hom.: 498155 Cov.: 59 AF XY: 0.825 AC XY: 599669 AN XY: 727100

African (AFR) AF: 0.498 AC: 16677 AN: 33470

American (AMR) AF: 0.695 AC: 31064 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.862 AC: 22516 AN: 26124

East Asian (EAS) AF: 0.936 AC: 37137 AN: 39660

South Asian (SAS) AF: 0.819 AC: 70678 AN: 86250

European-Finnish (FIN) AF: 0.800 AC: 42755 AN: 53416

Middle Eastern (MID) AF: 0.810 AC: 4667 AN: 5764

European-Non Finnish (NFE) AF: 0.835 AC: 928103 AN: 1111796

Other (OTH) AF: 0.817 AC: 49311 AN: 60374

GnomAD4 genome AF: 0.741 AC: 112687 AN: 151998 Hom.: 43385 Cov.: 31 AF XY: 0.744 AC XY: 55282 AN XY: 74316

African (AFR) AF: 0.514 AC: 21303 AN: 41420

American (AMR) AF: 0.760 AC: 11609 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.866 AC: 3008 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4848 AN: 5166

South Asian (SAS) AF: 0.820 AC: 3951 AN: 4816

European-Finnish (FIN) AF: 0.799 AC: 8450 AN: 10576

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.837 AC: 56852 AN: 67958

Other (OTH) AF: 0.761 AC: 1605 AN: 2110

Alfa AF: 0.804 Hom.: 172258

Bravo AF: 0.724

Asia WGS AF: 0.835 AC: 2905 AN: 3476

EpiCase AF: 0.837

EpiControl AF: 0.841

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 96% of patients studied by a panel of primary immunodeficiencies. Number of patients: 91. Only high quality variants are reported. -

Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Retinitis pigmentosa and erythrocytic microcytosis Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Benign:1

Oct 01, 2023

Dept Of Ophthalmology, Nagoya University

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.1
DANN	Benign	0.83
PhyloP100		0.91
Mutation Taster		=98/2	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: rs1705805; hg19: chr3-3189279; COSMIC: COSV51640888; COSMIC: COSV51640888;