19-4153755-C-T

Position:

• chr19-4153755-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_032607.3(CREB3L3):​c.8C>T​(p.Thr3Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CREB3L3 NM_032607.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.667

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027923554).
• BP6: Variant 19-4153755-C-T is Benign according to our data. Variant chr19-4153755-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2353462.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd4 at 5 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 rank	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10		NP_001258924.1
CREB3L3	NM_001271996.2	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10		NP_001258925.1
CREB3L3	NM_001271997.2	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 9		NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 10	1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.8C>T	p.Thr3Met	missense_variant	Exon 1 of 9	1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251160 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135790

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000489

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 40 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.0000289 AC XY: 21 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152094 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74304

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 3 of the CREB3L3 protein (p.Thr3Met). This variant is present in population databases (rs775663071, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CREB3L3-related conditions. ClinVar contains an entry for this variant (Variation ID: 2353462). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; 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. 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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	13
DANN	Benign	0.71
DEOGEN2	Benign	0.098	T;.;.;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.41	T;T;T;T
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.028	T;T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.38	N;.;.;.
REVEL	Uncertain	0.30
Sift	Benign	0.13	T;.;.;.
Sift4G	Benign	0.075	T;T;T;T
Polyphen		0.012	B;.;.;.
Vest4		0.047
MutPred		0.14		Loss of glycosylation at T3 (P = 0.0331);Loss of glycosylation at T3 (P = 0.0331);Loss of glycosylation at T3 (P = 0.0331);Loss of glycosylation at T3 (P = 0.0331);
MVP		0.36
MPC		0.10
ClinPred		0.038	T
GERP RS		-1.0
Varity_R		0.016
gMVP		0.19

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

Other links and lift over

dbSNP: rs775663071; hg19: chr19-4153752;