19-4154989-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_032607.3(CREB3L3):​c.118G>A​(p.Val40Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000023 in 1,611,890 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

CREB3L3
NM_032607.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.637
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17174938).
BS2
High AC in GnomAdExome4 at 33 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CREB3L3NM_032607.3 linkc.118G>A p.Val40Met missense_variant 2/10 ENST00000078445.7 NP_115996.1 Q68CJ9-1
CREB3L3NM_001271995.2 linkc.118G>A p.Val40Met missense_variant 2/10 NP_001258924.1 Q68CJ9-2
CREB3L3NM_001271996.2 linkc.118G>A p.Val40Met missense_variant 2/10 NP_001258925.1 Q68CJ9-4
CREB3L3NM_001271997.2 linkc.118G>A p.Val40Met missense_variant 2/9 NP_001258926.1 Q68CJ9-5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CREB3L3ENST00000078445.7 linkc.118G>A p.Val40Met missense_variant 2/101 NM_032607.3 ENSP00000078445.1 Q68CJ9-1
CREB3L3ENST00000595923.5 linkc.118G>A p.Val40Met missense_variant 2/101 ENSP00000469355.1 Q68CJ9-2
CREB3L3ENST00000602257.5 linkc.118G>A p.Val40Met missense_variant 2/101 ENSP00000472399.1 Q68CJ9-4
CREB3L3ENST00000602147.1 linkc.118G>A p.Val40Met missense_variant 2/91 ENSP00000470119.1 Q68CJ9-5

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000321
AC:
8
AN:
249522
Hom.:
1
AF XY:
0.0000518
AC XY:
7
AN XY:
135044
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:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000226
AC:
33
AN:
1459720
Hom.:
1
Cov.:
33
AF XY:
0.0000317
AC XY:
23
AN XY:
726264
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:
0.0000927
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000207
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74324
show subpopulations
Gnomad4 AFR
AF:
0.0000482
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:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000295
Hom.:
0
Bravo
AF:
0.0000264
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 17, 2023In 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 output the following: SIFT: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Not Available". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1907945). This variant has not been reported in the literature in individuals affected with CREB3L3-related conditions. This variant is present in population databases (rs376619280, gnomAD 0.01%), including at least one homozygous and/or hemizygous individual. This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 40 of the CREB3L3 protein (p.Val40Met). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.28
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
8.3
DANN
Benign
0.96
DEOGEN2
Benign
0.18
T;.;.;.
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.049
N
LIST_S2
Benign
0.85
D;D;D;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.17
T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Uncertain
2.1
M;M;M;M
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-0.74
N;.;.;.
REVEL
Benign
0.18
Sift
Benign
0.068
T;.;.;.
Sift4G
Benign
0.18
T;T;T;T
Polyphen
0.49
P;P;.;.
Vest4
0.28
MVP
0.79
MPC
0.48
ClinPred
0.088
T
GERP RS
1.4
Varity_R
0.035
gMVP
0.13

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.

Other links and lift over

dbSNP: rs376619280; hg19: chr19-4154986; API