rs566932471

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_016302.4(CRBN):c.1274C>T(p.Thr425Met) variant causes a missense change. The variant allele was found at a frequency of 0.000421 in 1,613,932 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00027 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00044 ( 10 hom. )

Consequence

CRBN
NM_016302.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 5.04

Publications

6 publications found

Variant links:

Genes affected

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 links:

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]

TRNT1 Gene-Disease associations (from GenCC):

congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
retinitis pigmentosa and erythrocytic microcytosis
Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

TRNT1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008156478).

BP6

Variant 3-3150920-G-A is Benign according to our data. Variant chr3-3150920-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 210759.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000269 (41/152272) while in subpopulation SAS AF = 0.00767 (37/4824). AF 95% confidence interval is 0.00572. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRBN	NM_016302.4 link	c.1274C>T	p.Thr425Met	missense_variant	Exon 11 of 11	ENST00000231948.9	NP_057386.2	Q96SW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRBN	ENST00000231948.9 link	c.1274C>T	p.Thr425Met	missense_variant	Exon 11 of 11	1	NM_016302.4	ENSP00000231948.4		Q96SW2-1

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000832

AC:

209

AN:

251180

AF XY:

0.00113

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000816

GnomAD4 exome

AF:

0.000436

AC:

638

AN:

1461660

Hom.:

Cov.:

AF XY:

0.000624

AC XY:

454

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.00688

AC:

593

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111908

Other (OTH)

AF:

0.000546

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

115

154

192

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000269

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00767

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000409

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000931

AC:

113

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 27, 2018

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CRBN-related disorder

Benign:1

Nov 22, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.044

.;T;.

Eigen

Benign

0.027

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Benign

0.0075

MetaRNN

Benign

0.0082

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.0

.;L;.

PhyloP100

5.0

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.1

.;N;N

REVEL

Benign

0.032

Sift

Benign

0.11

.;T;T

Sift4G

Benign

0.11

.;T;T

Polyphen

0.016, 0.028

.;B;B

Vest4

0.26, 0.26

MutPred

0.28

Gain of glycosylation at T429 (P = 0.0404);Gain of glycosylation at T429 (P = 0.0404);.;

MVP

0.71

MPC

0.21

ClinPred

0.037

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.074

gMVP

0.50

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over