19-4154954-T-G

Position:

chr19-4154954-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_ModerateBS2_Supporting

The NM_032607.3(CREB3L3):c.83T>G(p.Leu28Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000062 in 1,613,422 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

CREB3L3
NM_032607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.66

Variant links:

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]

CREB3L3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

BS2

High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L3	NM_032607.3 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10	ENST00000078445.7	NP_115996.1	Q68CJ9-1
CREB3L3	NM_001271995.2 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10		NP_001258924.1	Q68CJ9-2
CREB3L3	NM_001271996.2 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10		NP_001258925.1	Q68CJ9-4
CREB3L3	NM_001271997.2 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/9		NP_001258926.1	Q68CJ9-5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CREB3L3	ENST00000078445.7 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10	1	NM_032607.3	ENSP00000078445.1	Q68CJ9-1
CREB3L3	ENST00000595923.5 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10	1		ENSP00000469355.1	Q68CJ9-2
CREB3L3	ENST00000602257.5 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/10	1		ENSP00000472399.1	Q68CJ9-4
CREB3L3	ENST00000602147.1 linkuse as main transcript	c.83T>G	p.Leu28Arg	missense_variant	2/9	1		ENSP00000470119.1	Q68CJ9-5

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

251052

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135704

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461374

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726992

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74236

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CREB3L3-related conditions. This variant is present in population databases (rs368774801, gnomAD 0.01%). This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 28 of the CREB3L3 protein (p.Leu28Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.83

T;T;T;T

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.92

D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.9

M;M;M;M

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.3

D;.;.;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;.;.;.

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.85

MVP

0.99

MPC

0.62

ClinPred

0.97

GERP RS

5.2

Varity_R

0.68

gMVP

0.72

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over