11-46278221-G-A

Variant names:

• chr11-46278221-G-A
• rs1455815718
• NM_052854.4:c.102+8G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 2P and 10B. PM2 BP4_Strong BP6_Moderate BS1

The NM_052854.4(CREB3L1):​c.102+8G>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 0.00000288 in 1,386,516 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CREB3L1 NM_052854.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001429
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.65
• Publications: 0 publications found

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]

CREB3L1 Gene-Disease associations (from GenCC):

• osteogenesis imperfecta type 16

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 11-46278221-G-A is Benign according to our data. Variant chr11-46278221-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1551356.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000288 (4/1386516) while in subpopulation AMR AF = 0.000109 (4/36664). AF 95% confidence interval is 0.0000364. There are 0 homozygotes in GnomAdExome4. There are 1 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052854.4. 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
	CREB3L1	NM_052854.4	MANE Select	c.102+8G>A		splice_region intron	N/A	NP_443086.1	Q96BA8-1
	CREB3L1	NM_001425266.1		c.102+8G>A		splice_region intron	N/A	NP_001412195.1
	CREB3L1	NM_001425267.1		c.102+8G>A		splice_region intron	N/A	NP_001412196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L1	ENST00000621158.5	TSL:1 MANE Select	c.102+8G>A		splice_region intron	N/A	ENSP00000481956.1	Q96BA8-1
	CREB3L1	ENST00000862985.1		c.102+8G>A		splice_region intron	N/A	ENSP00000533044.1
	CREB3L1	ENST00000862986.1		c.102+8G>A		splice_region intron	N/A	ENSP00000533045.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000124 AC: 2 AN: 160896 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000288 AC: 4 AN: 1386516 Hom.: 0 Cov.: 26 AF XY: 0.00000146 AC XY: 1 AN XY: 686258

African (AFR) AF: 0.00 AC: 0 AN: 30984

American (AMR) AF: 0.000109 AC: 4 AN: 36664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24918

East Asian (EAS) AF: 0.00 AC: 0 AN: 34928

South Asian (SAS) AF: 0.00 AC: 0 AN: 78514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49472

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1067946

Other (OTH) AF: 0.00 AC: 0 AN: 57446

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.5
DANN	Benign	0.96
PhyloP100		-1.6

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.032
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: rs1455815718; hg19: chr11-46299772;