19-4154903-C-T

Position:

• chr19-4154903-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032607.3(CREB3L3):​c.32C>T​(p.Ala11Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,218 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: CREB3L3 NM_032607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB3L3	NM_032607.3	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10		NP_001258924.1
CREB3L3	NM_001271996.2	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10		NP_001258925.1
CREB3L3	NM_001271997.2	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 9		NP_001258926.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB3L3	ENST00000078445.7	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 10	1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.32C>T	p.Ala11Val	missense_variant	Exon 2 of 9	1		ENSP00000470119.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32

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

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

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

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 16, 2024

Variant summary: CREB3L3 c.32C>T (p.Ala11Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251188 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.32C>T in individuals affected with Hypertriglyceridemia 2 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.65	T;T;T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Uncertain	0.061	D
MutationAssessor	Uncertain	2.8	M;M;M;M
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.1	N;.;.;.
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Benign	0.11	T;T;T;D
Polyphen		0.89	P;P;.;.
Vest4		0.57
MutPred		0.29		Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);Loss of disorder (P = 0.0376);
MVP		0.97
MPC		0.23
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.25
gMVP		0.31

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

Other links and lift over

dbSNP: rs1403239207; hg19: chr19-4154900;