19-4154998-G-T

Position:

chr19-4154998-G-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_032607.3(CREB3L3):c.127G>T(p.Gly43Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000341 in 1,610,886 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

CREB3L3
NM_032607.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 3.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.758

BS2

High AC in GnomAdExome4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CREB3L3	NM_032607.3 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/10	ENST00000078445.7	NP_115996.1	Q68CJ9-1
CREB3L3	NM_001271995.2 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/10		NP_001258924.1	Q68CJ9-2
CREB3L3	NM_001271996.2 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/10		NP_001258925.1	Q68CJ9-4
CREB3L3	NM_001271997.2 linkuse as main transcript	c.127G>T	p.Gly43Cys	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.127G>T	p.Gly43Cys	missense_variant	2/10	1	NM_032607.3	ENSP00000078445.1	Q68CJ9-1
CREB3L3	ENST00000595923.5 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/10	1		ENSP00000469355.1	Q68CJ9-2
CREB3L3	ENST00000602257.5 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/10	1		ENSP00000472399.1	Q68CJ9-4
CREB3L3	ENST00000602147.1 linkuse as main transcript	c.127G>T	p.Gly43Cys	missense_variant	2/9	1		ENSP00000470119.1	Q68CJ9-5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.0000161

AC:

AN:

248484

Hom.:

AF XY:

0.0000223

AC XY:

AN XY:

134548

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000370

AC:

AN:

1458734

Hom.:

Cov.:

AF XY:

0.0000317

AC XY:

AN XY:

725778

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000351

Gnomad4 OTH exome

AF:

0.000215

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

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

Alfa

AF:

0.0000508

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CREB3L3-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 06, 2024

The CREB3L3 c.127G>T variant is predicted to result in the amino acid substitution p.Gly43Cys. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 08, 2023

This sequence change replaces glycine, which is neutral and non-polar, with cysteine, which is neutral and slightly polar, at codon 43 of the CREB3L3 protein (p.Gly43Cys). This variant is present in population databases (rs749442501, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CREB3L3-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CREB3L3 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Uncertain

0.029

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

D;.;.;.

Eigen

Benign

0.068

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.73

T;T;T;T

M_CAP

Uncertain

0.15

MetaRNN

Pathogenic

0.76

D;D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Uncertain

2.6

M;M;M;M

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-4.0

D;.;.;.

REVEL

Uncertain

0.36

Sift

Uncertain

0.014

D;.;.;.

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;D;.;.

Vest4

0.61

MutPred

0.56

Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);

MVP

0.95

MPC

0.48

ClinPred

0.92

GERP RS

1.8

Varity_R

0.23

gMVP

0.27

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

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