rs1378826731

Variant names:

• chr3-3144662-C-G
• rs1378826731
• NM_182916.3:c.560C>G

Your query was ambiguous. Multiple possible variants found:

• chr3-3144662-C-G
• chr3-3144662-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_182916.3(TRNT1):​c.560C>G​(p.Ala187Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,423,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A187V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TRNT1 NM_182916.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.73
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRNT1	NM_182916.3	c.560C>G	p.Ala187Gly	missense_variant	Exon 5 of 8	ENST00000251607.11	NP_886552.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRNT1	ENST00000251607.11	c.560C>G	p.Ala187Gly	missense_variant	Exon 5 of 8	1	NM_182916.3	ENSP00000251607.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1423596 Hom.: 0 Cov.: 29 AF XY: 0.00000141 AC XY: 1 AN XY: 708774

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32348

American (AMR) AF: 0.00 AC: 0 AN: 42406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25380

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38874

South Asian (SAS) AF: 0.00 AC: 0 AN: 83554

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1084038

Other (OTH) AF: 0.00 AC: 0 AN: 58688

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.88	D;D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.3	M;M
PhyloP100		7.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.39
Sift	Benign	0.074	T;T
Sift4G	Benign	0.087	T;T
Polyphen		0.80	P;B
Vest4		0.67
MutPred		0.76		Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);
MVP		0.47
MPC		0.013
ClinPred		0.98	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.81
Mutation Taster		=15/85	disease causing

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: rs1378826731; hg19: chr3-3186346;