rs606231287

Variant names:

• chr3-3144671-G-T
• rs606231287
• NM_182916.3:c.569G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-3144671-G-T
• chr3-3144671-G-C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_182916.3(TRNT1):​c.569G>T​(p.Arg190Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,413,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRNT1 NM_182916.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.77
• Publications: 9 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: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 3-3144671-G-T is Pathogenic according to our data. Variant chr3-3144671-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 157613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.569G>T	p.Arg190Ile	missense	Exon 5 of 8	NP_886552.3	Q96Q11-1
	TRNT1	NM_001367321.1		c.569G>T	p.Arg190Ile	missense	Exon 5 of 9	NP_001354250.1	Q96Q11-1
	TRNT1	NM_001367322.1		c.569G>T	p.Arg190Ile	missense	Exon 5 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.569G>T	p.Arg190Ile	missense	Exon 5 of 8	ENSP00000251607.6	Q96Q11-1
	TRNT1	ENST00000280591.10	TSL:1	c.569G>T	p.Arg190Ile	missense	Exon 5 of 8	ENSP00000280591.6	Q96Q11-2
	TRNT1	ENST00000698413.1		c.686G>T	p.Arg229Ile	missense	Exon 7 of 10	ENSP00000513706.1	A0A8V8TM71

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000425 AC: 1 AN: 235382 AF XY: 0.00000783

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000337

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1413630 Hom.: 0 Cov.: 29 AF XY: 0.00000426 AC XY: 3 AN XY: 703820

African (AFR) AF: 0.00 AC: 0 AN: 31838

American (AMR) AF: 0.0000248 AC: 1 AN: 40288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25066

East Asian (EAS) AF: 0.00 AC: 0 AN: 38824

South Asian (SAS) AF: 0.00 AC: 0 AN: 81828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1079276

Other (OTH) AF: 0.00 AC: 0 AN: 58328

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.8
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.76		Loss of MoRF binding (P = 0.0148)
MVP		0.96
MPC		0.017
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		0.96
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs606231287; hg19: chr3-3186355;