3-3174266-A-T

Variant names:

• chr3-3174266-A-T
• rs151039737
• NM_016302.4:c.175-5T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_016302.4(CRBN):​c.175-5T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,588,214 control chromosomes in the GnomAD database, including 328 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 32)
  • Exomes 𝑓: 0.013 (295 hom.)
• Consequence: CRBN NM_016302.4 splice_region, intron
• Scores: Splicing: ADA: 0.1779
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.478
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-3174266-A-T is Benign according to our data. Variant chr3-3174266-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1796/152308) while in subpopulation SAS AF = 0.0309 (149/4820). AF 95% confidence interval is 0.0269. There are 33 homozygotes in GnomAd4. There are 1052 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRBN	NM_016302.4	c.175-5T>A		splice_region_variant, intron_variant	Intron 2 of 10	ENST00000231948.9	NP_057386.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRBN	ENST00000231948.9	c.175-5T>A		splice_region_variant, intron_variant	Intron 2 of 10	1	NM_016302.4	ENSP00000231948.4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1796 AN: 152190 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00883

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0311

Gnomad FIN AF: 0.0577

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0170 AC: 4275 AN: 251172 AF XY: 0.0187

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00524

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0132 AC: 18939 AN: 1435906 Hom.: 295 Cov.: 26 AF XY: 0.0140 AC XY: 10053 AN XY: 716272

African (AFR) AF: 0.00127 AC: 42 AN: 33038

American (AMR) AF: 0.00573 AC: 256 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.0145 AC: 377 AN: 25978

East Asian (EAS) AF: 0.00149 AC: 59 AN: 39554

South Asian (SAS) AF: 0.0394 AC: 3379 AN: 85774

European-Finnish (FIN) AF: 0.0582 AC: 3109 AN: 53390

Middle Eastern (MID) AF: 0.0203 AC: 116 AN: 5716

European-Non Finnish (NFE) AF: 0.00988 AC: 10755 AN: 1088168

Other (OTH) AF: 0.0142 AC: 846 AN: 59608

GnomAD4 genome AF: 0.0118 AC: 1796 AN: 152308 Hom.: 33 Cov.: 32 AF XY: 0.0141 AC XY: 1052 AN XY: 74460

African (AFR) AF: 0.00178 AC: 74 AN: 41566

American (AMR) AF: 0.00882 AC: 135 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3472

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5184

South Asian (SAS) AF: 0.0309 AC: 149 AN: 4820

European-Finnish (FIN) AF: 0.0577 AC: 612 AN: 10608

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 729 AN: 68032

Other (OTH) AF: 0.0113 AC: 24 AN: 2116

Alfa AF: 0.0102 Hom.: 3

Bravo AF: 0.00704

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

May 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.69
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.63
SpliceAI score (max)		0.12		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: rs151039737; hg19: chr3-3215950;