19-4155001-G-T

Position:

• chr19-4155001-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.419

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]

ACMG classification

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
CREB3L3	NM_032607.3	c.130G>T	p.Glu44*	stop_gained	2/10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.130G>T	p.Glu44*	stop_gained	2/10		NP_001258924.1
CREB3L3	NM_001271996.2	c.130G>T	p.Glu44*	stop_gained	2/10		NP_001258925.1
CREB3L3	NM_001271997.2	c.130G>T	p.Glu44*	stop_gained	2/9		NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.130G>T	p.Glu44*	stop_gained	2/10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.130G>T	p.Glu44*	stop_gained	2/10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.130G>T	p.Glu44*	stop_gained	2/10	1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.130G>T	p.Glu44*	stop_gained	2/9	1		ENSP00000470119.1

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

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

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2022

This 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;