Genetic Variant CREB3L1:c.102+8G>T (chr11-46278221-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052854.4(CREB3L1):c.102+8G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

CREB3L1
NM_052854.4 splice_region, intron

Scores

Splicing: ADA: 0.00009300

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.65

Publications

0 publications found

Variant links:

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: Labcorp Genetics (formerly Invitae), Ambry Genetics
osteogenesis imperfecta type 3
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CREB3L1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CREB3L1	NM_052854.4	MANE Select	c.102+8G>T	splice_region intron	N/A	NP_443086.1	Q96BA8-1
CREB3L1	NM_001425266.1		c.102+8G>T	splice_region intron	N/A	NP_001412195.1
CREB3L1	NM_001425267.1		c.102+8G>T	splice_region intron	N/A	NP_001412196.1

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1386516

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686258

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30984

American (AMR)

AF:

0.00

AC:

AN:

36664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24918

East Asian (EAS)

AF:

0.00

AC:

AN:

34928

South Asian (SAS)

AF:

0.00

AC:

AN:

78514

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49472

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5644

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1067946

Other (OTH)

AF:

0.00

AC:

AN:

57446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

8.0

(source)

DANN

Benign

0.92

PhyloP100

-1.6

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000093

dbscSNV1_RF

Benign

0.042

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over