19-4154913-C-T

Position:

• chr19-4154913-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032607.3(CREB3L3):​c.42C>T​(p.Ala14Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 1,613,798 control chromosomes in the GnomAD database, including 12,482 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1065 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11417 hom.)
• Consequence: CREB3L3 NM_032607.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.100

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 19-4154913-C-T is Benign according to our data. Variant chr19-4154913-C-T is described in ClinVar as [Benign]. Clinvar id is 1243114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.128 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10		NP_001258924.1
CREB3L3	NM_001271996.2	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10		NP_001258925.1
CREB3L3	NM_001271997.2	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 9		NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 10	1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.42C>T	p.Ala14Ala	synonymous_variant	Exon 2 of 9	1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.112 AC: 17048 AN: 152102 Hom.: 1064 Cov.: 32

Gnomad AFR AF: 0.0895

Gnomad AMI AF: 0.158

Gnomad AMR AF: 0.0951

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0350

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.118

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.131

Gnomad OTH AF: 0.132

GnomAD3 exomes AF: 0.111 AC: 27834 AN: 251176 Hom.: 1730 AF XY: 0.114 AC XY: 15438 AN XY: 135774

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.0674

Gnomad ASJ exome AF: 0.164

Gnomad EAS exome AF: 0.0441

Gnomad SAS exome AF: 0.103

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.122 AC: 178312 AN: 1461580 Hom.: 11417 Cov.: 33 AF XY: 0.122 AC XY: 88943 AN XY: 727122

Gnomad4 AFR exome AF: 0.0888

Gnomad4 AMR exome AF: 0.0704

Gnomad4 ASJ exome AF: 0.169

Gnomad4 EAS exome AF: 0.0348

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.110

Gnomad4 NFE exome AF: 0.129

Gnomad4 OTH exome AF: 0.118

GnomAD4 genome AF: 0.112 AC: 17059 AN: 152218 Hom.: 1065 Cov.: 32 AF XY: 0.112 AC XY: 8304 AN XY: 74416

Gnomad4 AFR AF: 0.0895

Gnomad4 AMR AF: 0.0949

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.0351

Gnomad4 SAS AF: 0.101

Gnomad4 FIN AF: 0.118

Gnomad4 NFE AF: 0.131

Gnomad4 OTH AF: 0.133

Alfa AF: 0.125 Hom.: 721

Bravo AF: 0.110

Asia WGS AF: 0.0830 AC: 289 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.139

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	4.1
DANN	Benign	0.61

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: rs35474881; hg19: chr19-4154910; COSMIC: COSV50200686;