3-3174270-A-G

Variant names:

• chr3-3174270-A-G
• rs1669321
• NM_016302.4:c.175-9T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016302.4(CRBN):​c.175-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.98 in 1,600,996 control chromosomes in the GnomAD database, including 773,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.90 (63343 hom., cov: 31)
  • Exomes 𝑓: 0.99 (710237 hom.)
• Consequence: CRBN NM_016302.4 intron
• Scores: Splicing: ADA: 0.0001158
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.116
• Publications: 9 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 3-3174270-A-G is Benign according to our data. Variant chr3-3174270-A-G is described in ClinVar as Benign. ClinVar VariationId is 128855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.992 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRBN	NM_016302.4	c.175-9T>C		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.175-9T>C		intron_variant	Intron 2 of 10	1	NM_016302.4	ENSP00000231948.4

Frequencies

GnomAD3 genomes AF: 0.900 AC: 136852 AN: 152100 Hom.: 63314 Cov.: 31

Gnomad AFR AF: 0.655

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.998

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.959

Gnomad NFE AF: 0.998

Gnomad OTH AF: 0.925

GnomAD2 exomes AF: 0.972 AC: 244286 AN: 251212 AF XY: 0.980

Gnomad AFR exome AF: 0.642

Gnomad AMR exome AF: 0.978

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.998

Gnomad OTH exome AF: 0.985

GnomAD4 exome AF: 0.989 AC: 1432312 AN: 1448778 Hom.: 710237 Cov.: 28 AF XY: 0.990 AC XY: 714726 AN XY: 721786

African (AFR) AF: 0.638 AC: 21129 AN: 33112

American (AMR) AF: 0.975 AC: 43592 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 25898 AN: 26042

East Asian (EAS) AF: 1.00 AC: 39635 AN: 39636

South Asian (SAS) AF: 0.999 AC: 85894 AN: 85982

European-Finnish (FIN) AF: 1.00 AC: 53394 AN: 53394

Middle Eastern (MID) AF: 0.978 AC: 5615 AN: 5744

European-Non Finnish (NFE) AF: 0.999 AC: 1098723 AN: 1100230

Other (OTH) AF: 0.975 AC: 58432 AN: 59930

GnomAD4 genome AF: 0.900 AC: 136937 AN: 152218 Hom.: 63343 Cov.: 31 AF XY: 0.904 AC XY: 67269 AN XY: 74408

African (AFR) AF: 0.656 AC: 27195 AN: 41480

American (AMR) AF: 0.957 AC: 14631 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3456 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5176 AN: 5176

South Asian (SAS) AF: 0.998 AC: 4813 AN: 4822

European-Finnish (FIN) AF: 1.00 AC: 10613 AN: 10614

Middle Eastern (MID) AF: 0.963 AC: 283 AN: 294

European-Non Finnish (NFE) AF: 0.998 AC: 67899 AN: 68040

Other (OTH) AF: 0.926 AC: 1959 AN: 2116

Alfa AF: 0.949 Hom.: 30212

Bravo AF: 0.884

Asia WGS AF: 0.980 AC: 3408 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 30, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

Dec 27, 2012

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, autosomal recessive 2 Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.2
DANN	Benign	0.66
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.050		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: rs1669321; hg19: chr3-3215954;