rs797045481

Variant names:

• chr3-3174150-T-C
• rs797045481
• NM_016302.4:c.286A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016302.4(CRBN):​c.286A>G​(p.Thr96Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRBN NM_016302.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.83
• Publications: 0 publications found

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 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016302.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	NM_016302.4	MANE Select	c.286A>G	p.Thr96Ala	missense	Exon 3 of 11	NP_057386.2
	CRBN	NM_001173482.1		c.283A>G	p.Thr95Ala	missense	Exon 3 of 11	NP_001166953.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	ENST00000231948.9	TSL:1 MANE Select	c.286A>G	p.Thr96Ala	missense	Exon 3 of 11	ENSP00000231948.4
	CRBN	ENST00000432408.6	TSL:1	c.283A>G	p.Thr95Ala	missense	Exon 3 of 11	ENSP00000412499.2
	CRBN	ENST00000450014.1	TSL:1	c.271A>G	p.Thr91Ala	missense	Exon 3 of 5	ENSP00000392073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.8
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.86
MutPred		0.51		Loss of glycosylation at P98 (P = 0.0567)
MVP		0.70
MPC		0.44
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.49
gMVP		0.83
Mutation Taster		=23/77	disease causing

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: rs797045481; hg19: chr3-3215834;