3-3151021-ACA-GCG

Variant names:

• chr3-3151021-ACA-GCG
• NM_016302.4:c.1171_1173delTGTinsCGC
• CRBN p.Cys391Arg

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PS1_Very_Strong PP3

The NM_016302.4(CRBN):​c.1171_1173delTGTinsCGC​(p.Cys391Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRBN NM_016302.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.11
• 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]

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: Laboratory for Molecular Medicine, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)
• retinitis pigmentosa and erythrocytic microcytosis

  Inheritance: AR Classification: STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PS1: Transcript NM_016302.4 (CRBN) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	NM_016302.4	MANE Select	c.1171_1173delTGTinsCGC	p.Cys391Arg	missense	N/A	NP_057386.2
	CRBN	NM_001173482.1		c.1168_1170delTGTinsCGC	p.Cys390Arg	missense	N/A	NP_001166953.1	Q96SW2-2
	TRNT1	NM_001367321.1		c.*515_*517delACAinsGCG		3_prime_UTR	Exon 9 of 9	NP_001354250.1	Q96Q11-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CRBN	ENST00000231948.9	TSL:1 MANE Select	c.1171_1173delTGTinsCGC	p.Cys391Arg	missense	N/A	ENSP00000231948.4	Q96SW2-1
	CRBN	ENST00000432408.6	TSL:1	c.1168_1170delTGTinsCGC	p.Cys390Arg	missense	N/A	ENSP00000412499.2	Q96SW2-2
	CRBN	ENST00000488263.5	TSL:1	n.3516_3518delTGTinsCGC		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr3-3192705;