19-4153662-G-A

Position:

• chr19-4153662-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032607.3(CREB3L3):​c.-86G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.767 in 1,555,886 control chromosomes in the GnomAD database, including 459,878 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (50793 hom., cov: 31)
  • Exomes 𝑓: 0.76 (409085 hom.)
• Consequence: CREB3L3 NM_032607.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 19-4153662-G-A is Benign according to our data. Variant chr19-4153662-G-A is described in ClinVar as [Benign]. Clinvar id is 1225039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.932 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.-86G>A		5_prime_UTR_variant	1/10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.-86G>A		5_prime_UTR_variant	1/10		NP_001258924.1
CREB3L3	NM_001271996.2	c.-86G>A		5_prime_UTR_variant	1/10		NP_001258925.1
CREB3L3	NM_001271997.2	c.-86G>A		5_prime_UTR_variant	1/9		NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445	c.-86G>A		5_prime_UTR_variant	1/10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923	c.-86G>A		5_prime_UTR_variant	1/10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.-86G>A		upstream_gene_variant		1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.-86G>A		upstream_gene_variant		1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.812 AC: 123399 AN: 151970 Hom.: 50735 Cov.: 31

Gnomad AFR AF: 0.940

Gnomad AMI AF: 0.638

Gnomad AMR AF: 0.830

Gnomad ASJ AF: 0.764

Gnomad EAS AF: 0.906

Gnomad SAS AF: 0.799

Gnomad FIN AF: 0.737

Gnomad MID AF: 0.778

Gnomad NFE AF: 0.741

Gnomad OTH AF: 0.806

GnomAD4 exome AF: 0.762 AC: 1069282 AN: 1403798 Hom.: 409085 Cov.: 22 AF XY: 0.760 AC XY: 532500 AN XY: 700288

Gnomad4 AFR exome AF: 0.946

Gnomad4 AMR exome AF: 0.869

Gnomad4 ASJ exome AF: 0.766

Gnomad4 EAS exome AF: 0.898

Gnomad4 SAS exome AF: 0.779

Gnomad4 FIN exome AF: 0.731

Gnomad4 NFE exome AF: 0.746

Gnomad4 OTH exome AF: 0.776

GnomAD4 genome AF: 0.812 AC: 123515 AN: 152088 Hom.: 50793 Cov.: 31 AF XY: 0.814 AC XY: 60483 AN XY: 74336

Gnomad4 AFR AF: 0.940

Gnomad4 AMR AF: 0.830

Gnomad4 ASJ AF: 0.764

Gnomad4 EAS AF: 0.906

Gnomad4 SAS AF: 0.798

Gnomad4 FIN AF: 0.737

Gnomad4 NFE AF: 0.741

Gnomad4 OTH AF: 0.809

Alfa AF: 0.760 Hom.: 41265

Bravo AF: 0.828

Asia WGS AF: 0.868 AC: 3019 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.67
DANN	Benign	0.54
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs350879; hg19: chr19-4153659;