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: 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=-0.54).
• 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.

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.948A>G	p.Ala316Ala	synonymous	Exon 7 of 8	NP_886552.3	Q96Q11-1
	TRNT1	NM_001367321.1		c.948A>G	p.Ala316Ala	synonymous	Exon 7 of 9	NP_001354250.1	Q96Q11-1
	TRNT1	NM_001367322.1		c.948A>G	p.Ala316Ala	synonymous	Exon 7 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.948A>G	p.Ala316Ala	synonymous	Exon 7 of 8	ENSP00000251607.6	Q96Q11-1
	TRNT1	ENST00000280591.10	TSL:1	c.888A>G	p.Ala296Ala	synonymous	Exon 7 of 8	ENSP00000280591.6	Q96Q11-2
	TRNT1	ENST00000698413.1		c.1065A>G	p.Ala355Ala	synonymous	Exon 9 of 10	ENSP00000513706.1	A0A8V8TM71

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome (2)
-	-	1	not provided (2)
-	-	1	Retinal dystrophy (1)
-	-	1	Retinitis pigmentosa and erythrocytic microcytosis (1)

Computational scores

Source: dbNSFP v4.9

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;