19-4154920-A-G

Position:

• chr19-4154920-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BS2_Supporting

The NM_032607.3(CREB3L3):​c.49A>G​(p.Met17Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CREB3L3 NM_032607.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.82

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14241266).
• BS2: High AC in GnomAdExome4 at 8 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.49A>G	p.Met17Val	missense_variant	Exon 2 of 10	ENST00000078445.7	NP_115996.1
CREB3L3	NM_001271995.2	c.49A>G	p.Met17Val	missense_variant	Exon 2 of 10		NP_001258924.1
CREB3L3	NM_001271996.2	c.49A>G	p.Met17Val	missense_variant	Exon 2 of 10		NP_001258925.1
CREB3L3	NM_001271997.2	c.49A>G	p.Met17Val	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.49A>G	p.Met17Val	missense_variant	Exon 2 of 10	1	NM_032607.3	ENSP00000078445.1
CREB3L3	ENST00000595923.5	c.49A>G	p.Met17Val	missense_variant	Exon 2 of 10	1		ENSP00000469355.1
CREB3L3	ENST00000602257.5	c.49A>G	p.Met17Val	missense_variant	Exon 2 of 10	1		ENSP00000472399.1
CREB3L3	ENST00000602147.1	c.49A>G	p.Met17Val	missense_variant	Exon 2 of 9	1		ENSP00000470119.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251228 Hom.: 0 AF XY: 0.00000736 AC XY: 1 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: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461666 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727146

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: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000824 AC: 1

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

Ambry Genetics

Feb 07, 2023

Does not currently meet published gene-disease clinical validity criteria for this gene 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	Benign	0.058
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.0010
DANN	Benign	0.58
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.38	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.20	N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.4	N;.;.;.
REVEL	Benign	0.18
Sift	Benign	0.20	T;.;.;.
Sift4G	Benign	0.42	T;T;T;T
Polyphen		0.0	B;B;.;.
Vest4		0.22
MutPred		0.29		Loss of disorder (P = 0.085);Loss of disorder (P = 0.085);Loss of disorder (P = 0.085);Loss of disorder (P = 0.085);
MVP		0.59
MPC		0.10
ClinPred		0.090	T
GERP RS		-6.5
Varity_R		0.058
gMVP		0.18

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: rs755516505; hg19: chr19-4154917;