rs1669348

Variant names:

• chr3-3147714-A-G
• rs1669348
• NM_182916.3:c.1056+11A>G

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.1056+11A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.607 in 1,597,412 control chromosomes in the GnomAD database, including 304,705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23076 hom., cov: 32)
  • Exomes 𝑓: 0.61 (281629 hom.)
• Consequence: TRNT1 NM_182916.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.271
• Publications: 15 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 3-3147714-A-G is Benign according to our data. Variant chr3-3147714-A-G is described in ClinVar as Benign. ClinVar VariationId is 380146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.653 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.1056+11A>G		intron	N/A	NP_886552.3	Q96Q11-1
	TRNT1	NM_001367321.1		c.1056+11A>G		intron	N/A	NP_001354250.1	Q96Q11-1
	TRNT1	NM_001367322.1		c.1056+11A>G		intron	N/A	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.1056+11A>G		intron	N/A	ENSP00000251607.6	Q96Q11-1
	TRNT1	ENST00000280591.10	TSL:1	c.996+11A>G		intron	N/A	ENSP00000280591.6	Q96Q11-2
	CRBN	ENST00000639284.1	TSL:5	c.1312-2215T>C		intron	N/A	ENSP00000491442.1	A0A1W2PPJ5

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80819 AN: 151898 Hom.: 23082 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.726

Gnomad AMR AF: 0.472

Gnomad ASJ AF: 0.705

Gnomad EAS AF: 0.199

Gnomad SAS AF: 0.443

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.658

Gnomad OTH AF: 0.584

GnomAD2 exomes AF: 0.543 AC: 130231 AN: 240004 AF XY: 0.556

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.371

Gnomad ASJ exome AF: 0.702

Gnomad EAS exome AF: 0.218

Gnomad FIN exome AF: 0.574

Gnomad NFE exome AF: 0.664

Gnomad OTH exome AF: 0.606

GnomAD4 exome AF: 0.614 AC: 888059 AN: 1445396 Hom.: 281629 Cov.: 36 AF XY: 0.613 AC XY: 440417 AN XY: 718032

African (AFR) AF: 0.357 AC: 11614 AN: 32564

American (AMR) AF: 0.378 AC: 15693 AN: 41468

Ashkenazi Jewish (ASJ) AF: 0.693 AC: 17661 AN: 25492

East Asian (EAS) AF: 0.184 AC: 7250 AN: 39448

South Asian (SAS) AF: 0.478 AC: 39936 AN: 83612

European-Finnish (FIN) AF: 0.578 AC: 30623 AN: 53020

Middle Eastern (MID) AF: 0.681 AC: 3866 AN: 5676

European-Non Finnish (NFE) AF: 0.657 AC: 725528 AN: 1104476

Other (OTH) AF: 0.602 AC: 35888 AN: 59640

GnomAD4 genome AF: 0.532 AC: 80829 AN: 152016 Hom.: 23076 Cov.: 32 AF XY: 0.522 AC XY: 38823 AN XY: 74314

African (AFR) AF: 0.367 AC: 15215 AN: 41468

American (AMR) AF: 0.471 AC: 7199 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.705 AC: 2446 AN: 3468

East Asian (EAS) AF: 0.200 AC: 1036 AN: 5182

South Asian (SAS) AF: 0.442 AC: 2131 AN: 4816

European-Finnish (FIN) AF: 0.568 AC: 6006 AN: 10568

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44699 AN: 67934

Other (OTH) AF: 0.584 AC: 1230 AN: 2106

Alfa AF: 0.599 Hom.: 13047

Bravo AF: 0.515

Asia WGS AF: 0.342 AC: 1192 AN: 3476

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 (1)
-	-	1	Retinitis pigmentosa and erythrocytic microcytosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	5.7
DANN	Benign	0.70
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1669348; hg19: chr3-3189398; COSMIC: COSV51640955; COSMIC: COSV51640955;