19-4155001-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_032607.3(CREB3L3):​c.130G>T​(p.Glu44*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,420 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CREB3L3
NM_032607.3 stop_gained

Scores

2
1
4

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.419
Variant links:
Genes affected
CREB3L3 (HGNC:18855): (cAMP responsive element binding protein 3 like 3) This gene encodes a member of the basic-leucine zipper family and the AMP-dependent transcription factor family. The encoded protein is localized to the endoplasmic reticulum and acts as a transcription factor activated by cyclic AMP stimulation. The encoded protein binds the cyclic AMP response element (CRE) and the box-B element and has been linked to acute inflammatory response, hepatocellular carcinoma, triglyceride metabolism, and hepcidin expression. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-4155001-G-T is Pathogenic according to our data. Variant chr19-4155001-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 1943961.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CREB3L3NM_032607.3 linkc.130G>T p.Glu44* stop_gained 2/10 ENST00000078445.7 NP_115996.1 Q68CJ9-1
CREB3L3NM_001271995.2 linkc.130G>T p.Glu44* stop_gained 2/10 NP_001258924.1 Q68CJ9-2
CREB3L3NM_001271996.2 linkc.130G>T p.Glu44* stop_gained 2/10 NP_001258925.1 Q68CJ9-4
CREB3L3NM_001271997.2 linkc.130G>T p.Glu44* stop_gained 2/9 NP_001258926.1 Q68CJ9-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CREB3L3ENST00000078445.7 linkc.130G>T p.Glu44* stop_gained 2/101 NM_032607.3 ENSP00000078445.1 Q68CJ9-1
CREB3L3ENST00000595923.5 linkc.130G>T p.Glu44* stop_gained 2/101 ENSP00000469355.1 Q68CJ9-2
CREB3L3ENST00000602257.5 linkc.130G>T p.Glu44* stop_gained 2/101 ENSP00000472399.1 Q68CJ9-4
CREB3L3ENST00000602147.1 linkc.130G>T p.Glu44* stop_gained 2/91 ENSP00000470119.1 Q68CJ9-5

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458420
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
725636
show subpopulations
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

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 02, 2022This sequence change creates a premature translational stop signal (p.Glu44*) in the CREB3L3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CREB3L3 are known to be pathogenic (PMID: 21666694, 26427795). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CREB3L3-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.28
CADD
Pathogenic
33
DANN
Uncertain
0.99
Eigen
Benign
0.15
Eigen_PC
Benign
-0.19
FATHMM_MKL
Benign
0.11
N
Vest4
0.84
GERP RS
3.0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4154998; API