19-4154974-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP3BS2_Supporting

The NM_032607.3(CREB3L3):​c.103G>A​(p.Gly35Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000018 in 1,612,974 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 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

CREB3L3
NM_032607.3 missense

Scores

2
11
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.23
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 Uncertain_significance. Variant got 0 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.82
BS2
High AC in GnomAd4 at 7 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
CREB3L3NM_032607.3 linkc.103G>A p.Gly35Ser missense_variant 2/10 ENST00000078445.7 NP_115996.1 Q68CJ9-1
CREB3L3NM_001271995.2 linkc.103G>A p.Gly35Ser missense_variant 2/10 NP_001258924.1 Q68CJ9-2
CREB3L3NM_001271996.2 linkc.103G>A p.Gly35Ser missense_variant 2/10 NP_001258925.1 Q68CJ9-4
CREB3L3NM_001271997.2 linkc.103G>A p.Gly35Ser 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.103G>A p.Gly35Ser missense_variant 2/101 NM_032607.3 ENSP00000078445.1 Q68CJ9-1
CREB3L3ENST00000595923.5 linkc.103G>A p.Gly35Ser missense_variant 2/101 ENSP00000469355.1 Q68CJ9-2
CREB3L3ENST00000602257.5 linkc.103G>A p.Gly35Ser missense_variant 2/101 ENSP00000472399.1 Q68CJ9-4
CREB3L3ENST00000602147.1 linkc.103G>A p.Gly35Ser missense_variant 2/91 ENSP00000470119.1 Q68CJ9-5

Frequencies

GnomAD3 genomes
AF:
0.0000460
AC:
7
AN:
152126
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000400
AC:
10
AN:
250270
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135362
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000867
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:
0.00
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000151
AC:
22
AN:
1460730
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
726694
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000719
Gnomad4 OTH exome
AF:
0.0000828
GnomAD4 genome
AF:
0.0000460
AC:
7
AN:
152244
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74440
show subpopulations
Gnomad4 AFR
AF:
0.0000963
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000528
Hom.:
0
Bravo
AF:
0.0000718
ESP6500AA
AF:
0.000454
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 27, 2021The c.103G>A (p.G35S) alteration is located in exon 2 (coding exon 2) of the CREB3L3 gene. This alteration results from a G to A substitution at nucleotide position 103, causing the glycine (G) at amino acid position 35 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Benign
-0.073
T
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.33
T;.;.;.
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.88
D;D;D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.82
D;D;D;D
MetaSVM
Uncertain
0.70
D
MutationAssessor
Uncertain
2.5
M;M;M;M
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.5
D;.;.;.
REVEL
Uncertain
0.59
Sift
Benign
0.034
D;.;.;.
Sift4G
Benign
0.46
T;T;T;T
Polyphen
1.0
D;D;.;.
Vest4
0.67
MVP
0.99
MPC
0.51
ClinPred
0.18
T
GERP RS
5.2
Varity_R
0.23
gMVP
0.49

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: rs201474344; hg19: chr19-4154971; COSMIC: COSV50181642; API