rs1555222973

Positions:

• chr11-46312635-TAAG-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM4_Supporting PP5_Moderate

The ENST00000621158.5(CREB3L1):​c.934_936del​(p.Lys312del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CREB3L1 ENST00000621158.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 9.01

Genes affected

CREB3L1 (HGNC:18856): (cAMP responsive element binding protein 3 like 1) The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER). However, upon stress to the ER, the encoded protein is cleaved and the released cytoplasmic transcription factor domain translocates to the nucleus. There it activates the transcription of target genes by binding to box-B elements. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000621158.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 11-46312635-TAAG-T is Pathogenic according to our data. Variant chr11-46312635-TAAG-T is described in ClinVar as [Pathogenic]. Clinvar id is 559483.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L1	NM_052854.4	c.934_936del	p.Lys312del	inframe_deletion	7/12	ENST00000621158.5	NP_443086.1
CREB3L1	XM_006718380.4	c.934_936del	p.Lys312del	inframe_deletion	7/9		XP_006718443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L1	ENST00000621158.5	c.934_936del	p.Lys312del	inframe_deletion	7/12	1	NM_052854.4	ENSP00000481956	P1
CREB3L1	ENST00000530518.1	c.214_216del	p.Lys72del	inframe_deletion	3/5	2		ENSP00000436574
CREB3L1	ENST00000527342.1			downstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459624 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 725878

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta Pathogenic:2

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Pathogenic, criteria provided, single submitter	in vitro;research	Collagen Diagnostic Laboratory, University of Washington	-	An individual homozygous for the variant exhibited a severe OI-like phenotype with long bone deformities and in utero fractures consistent with OI Type II. Multiple individuals heterozygous for the variant exhibited mild OI-like phenotypes including blue sclerae, osteopenia, and fractures consistent with OI Type I. A history of fractures is shared by individuals going back several generations. -

Osteogenesis imperfecta type 16 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 07, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555222973; hg19: chr11-46334186;