3-3174046-T-G

Variant names:

• chr3-3174046-T-G
• rs115124101
• NM_016302.4:c.377+13A>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_016302.4(CRBN):​c.377+13A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,606,866 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.012 (33 hom., cov: 32)
  • Exomes 𝑓: 0.013 (286 hom.)
• Consequence: CRBN NM_016302.4 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.100
• 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0118 (1797/152286) while in subpopulation SAS AF = 0.0307 (148/4828). AF 95% confidence interval is 0.0266. There are 33 homozygotes in GnomAd4. There are 1053 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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.377+13A>C		intron_variant	Intron 3 of 10	ENST00000231948.9	NP_057386.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRBN	ENST00000231948.9	c.377+13A>C		intron_variant	Intron 3 of 10	1	NM_016302.4	ENSP00000231948.4

Frequencies

GnomAD3 genomes AF: 0.0118 AC: 1797 AN: 152168 Hom.: 33 Cov.: 32

Gnomad AFR AF: 0.00179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00884

Gnomad ASJ AF: 0.0138

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0308

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: 4268 AN: 251286 AF XY: 0.0187

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.00523

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00272

Gnomad FIN exome AF: 0.0614

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.0194

GnomAD4 exome AF: 0.0130 AC: 18885 AN: 1454580 Hom.: 286 Cov.: 28 AF XY: 0.0138 AC XY: 10022 AN XY: 724200

African (AFR) AF: 0.00126 AC: 42 AN: 33352

American (AMR) AF: 0.00570 AC: 255 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 375 AN: 26076

East Asian (EAS) AF: 0.00146 AC: 58 AN: 39658

South Asian (SAS) AF: 0.0392 AC: 3374 AN: 86098

European-Finnish (FIN) AF: 0.0581 AC: 3099 AN: 53318

Middle Eastern (MID) AF: 0.0207 AC: 119 AN: 5754

European-Non Finnish (NFE) AF: 0.00970 AC: 10722 AN: 1105500

Other (OTH) AF: 0.0140 AC: 841 AN: 60112

GnomAD4 genome AF: 0.0118 AC: 1797 AN: 152286 Hom.: 33 Cov.: 32 AF XY: 0.0141 AC XY: 1053 AN XY: 74466

African (AFR) AF: 0.00178 AC: 74 AN: 41558

American (AMR) AF: 0.00882 AC: 135 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 48 AN: 3466

East Asian (EAS) AF: 0.00309 AC: 16 AN: 5180

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4828

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: 731 AN: 68024

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

Alfa AF: 0.0107 Hom.: 1

Bravo AF: 0.00704

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.1
DANN	Benign	0.62
PhyloP100		0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs115124101; hg19: chr3-3215730;