19-4154849-G-A

Position:

• chr19-4154849-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.28-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,612,370 control chromosomes in the GnomAD database, including 1,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (726 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (657 hom.)
• Consequence: CREB3L3 NM_032607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.648

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=-0.82).
• BP6: Variant 19-4154849-G-A is Benign according to our data. Variant chr19-4154849-G-A is described in ClinVar as [Benign]. Clinvar id is 1174301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.28-50G>A		intron_variant		ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.28-50G>A		intron_variant			NP_001258924.1
CREB3L3	NM_001271996.2	c.28-50G>A		intron_variant			NP_001258925.1
CREB3L3	NM_001271997.2	c.28-50G>A		intron_variant			NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.28-50G>A		intron_variant		1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.28-50G>A		intron_variant		1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.28-50G>A		intron_variant		1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.28-50G>A		intron_variant		1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7985 AN: 152128 Hom.: 726 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0469

GnomAD3 exomes AF: 0.0132 AC: 3298 AN: 249414 Hom.: 276 AF XY: 0.00958 AC XY: 1294 AN XY: 135008

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.00694

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00524 AC: 7657 AN: 1460124 Hom.: 657 Cov.: 31 AF XY: 0.00441 AC XY: 3206 AN XY: 726438

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.00816

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0525 AC: 7997 AN: 152246 Hom.: 726 Cov.: 32 AF XY: 0.0512 AC XY: 3808 AN XY: 74446

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0163

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0464

Alfa AF: 0.0247 Hom.: 76

Bravo AF: 0.0599

Asia WGS AF: 0.00693 AC: 25 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 11, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4081614; hg19: chr19-4154846;