chr19-4153859-T-C

Position:

• chr19-4153859-T-C

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.27+85T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 1,426,270 control chromosomes in the GnomAD database, including 8,454 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (942 hom., cov: 31)
  • Exomes 𝑓: 0.099 (7512 hom.)
• Consequence: CREB3L3 NM_032607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.273

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=-0.81).
• BP6: Variant 19-4153859-T-C is Benign according to our data. Variant chr19-4153859-T-C is described in ClinVar as [Benign]. Clinvar id is 1224798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.27+85T>C		intron_variant		ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.27+85T>C		intron_variant			NP_001258924.1
CREB3L3	NM_001271996.2	c.27+85T>C		intron_variant			NP_001258925.1
CREB3L3	NM_001271997.2	c.27+85T>C		intron_variant			NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.27+85T>C		intron_variant		1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.27+85T>C		intron_variant		1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.27+85T>C		intron_variant		1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.27+85T>C		intron_variant		1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.0961 AC: 14587 AN: 151856 Hom.: 937 Cov.: 31

Gnomad AFR AF: 0.0531

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.255

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0885

Gnomad OTH AF: 0.0927

GnomAD4 exome AF: 0.0988 AC: 125886 AN: 1274296 Hom.: 7512 AF XY: 0.0981 AC XY: 62871 AN XY: 640886

Gnomad4 AFR exome AF: 0.0518

Gnomad4 AMR exome AF: 0.244

Gnomad4 ASJ exome AF: 0.102

Gnomad4 EAS exome AF: 0.260

Gnomad4 SAS exome AF: 0.0957

Gnomad4 FIN exome AF: 0.0980

Gnomad4 NFE exome AF: 0.0877

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.0962 AC: 14615 AN: 151974 Hom.: 942 Cov.: 31 AF XY: 0.100 AC XY: 7431 AN XY: 74270

Gnomad4 AFR AF: 0.0532

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.101

Gnomad4 EAS AF: 0.255

Gnomad4 SAS AF: 0.102

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.0885

Gnomad4 OTH AF: 0.0927

Alfa AF: 0.0936 Hom.: 137

Bravo AF: 0.101

Asia WGS AF: 0.189 AC: 654 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	clinical testing	GeneDx	May 10, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.0
DANN	Benign	0.73

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

LitVar

Other links and lift over

dbSNP: rs350878; hg19: chr19-4153856; COSMIC: COSV50254941;