NM_052854.4:c.488C>T

Variant names:

• chr11-46307972-C-T
• rs747612049
• NM_052854.4:c.488C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS1_Supporting

The NM_052854.4(CREB3L1):​c.488C>T​(p.Pro163Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000513 in 1,559,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P163R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: CREB3L1 NM_052854.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.13
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.772
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000461 (7/151954) while in subpopulation AFR AF = 0.000169 (7/41360). AF 95% confidence interval is 0.0000791. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.488C>T	p.Pro163Leu	missense	Exon 3 of 12	NP_443086.1	Q96BA8-1
	CREB3L1	NM_001425266.1		c.488C>T	p.Pro163Leu	missense	Exon 3 of 12	NP_001412195.1
	CREB3L1	NM_001425267.1		c.482C>T	p.Pro161Leu	missense	Exon 3 of 12	NP_001412196.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L1	ENST00000621158.5	TSL:1 MANE Select	c.488C>T	p.Pro163Leu	missense	Exon 3 of 12	ENSP00000481956.1	Q96BA8-1
	CREB3L1	ENST00000862985.1		c.488C>T	p.Pro163Leu	missense	Exon 3 of 12	ENSP00000533044.1
	CREB3L1	ENST00000862986.1		c.332-3060C>T		intron	N/A	ENSP00000533045.1

Frequencies

GnomAD3 genomes AF: 0.0000461 AC: 7 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000591 AC: 1 AN: 169102 AF XY: 0.0000108

Gnomad AFR exome AF: 0.000111

Gnomad AMR exome AF: 0.00

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: 7.11e-7 AC: 1 AN: 1407136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 695842

African (AFR) AF: 0.0000319 AC: 1 AN: 31346

American (AMR) AF: 0.00 AC: 0 AN: 35736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24804

East Asian (EAS) AF: 0.00 AC: 0 AN: 36616

South Asian (SAS) AF: 0.00 AC: 0 AN: 79730

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086510

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome AF: 0.0000461 AC: 7 AN: 151954 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74230

African (AFR) AF: 0.000169 AC: 7 AN: 41360

American (AMR) AF: 0.00 AC: 0 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000166 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.00000850 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.1
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.59
ClinPred		0.79	D
GERP RS		4.8
Varity_R		0.29
gMVP		0.52
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs747612049; hg19: chr11-46329523; COSMIC: COSV55830662; COSMIC: COSV55830662;