rs4081614

Variant names:

• chr19-4154849-G-A
• rs4081614
• NM_032607.3:c.28-50G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-4154849-G-A
• chr19-4154849-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032607.3(CREB3L3):​c.28-50G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00971 in 1,612,370 control chromosomes in the GnomAD database, including 1,383 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.053 (726 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (657 hom.)
• Consequence: CREB3L3 NM_032607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.648
• Publications: 1 publications found

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]

CREB3L3 Gene-Disease associations (from GenCC):

• hypertriglyceridemia

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• hypertriglyceridemia 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hypertriglyceridemia 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-4154849-G-A is Benign according to our data. Variant chr19-4154849-G-A is described in ClinVar as Benign. ClinVar VariationId is 1174301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032607.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L3	NM_032607.3	MANE Select	c.28-50G>A		intron	N/A	NP_115996.1	Q68CJ9-1
	CREB3L3	NM_001271995.2		c.28-50G>A		intron	N/A	NP_001258924.1	Q68CJ9-2
	CREB3L3	NM_001271996.2		c.28-50G>A		intron	N/A	NP_001258925.1	Q68CJ9-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L3	ENST00000078445.7	TSL:1 MANE Select	c.28-50G>A		intron	N/A	ENSP00000078445.1	Q68CJ9-1
	CREB3L3	ENST00000595923.5	TSL:1	c.28-50G>A		intron	N/A	ENSP00000469355.1	Q68CJ9-2
	CREB3L3	ENST00000602257.5	TSL:1	c.28-50G>A		intron	N/A	ENSP00000472399.1	Q68CJ9-4

Frequencies

GnomAD3 genomes AF: 0.0525 AC: 7985 AN: 152128 Hom.: 726 Cov.: 32

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0469

GnomAD2 exomes AF: 0.0132 AC: 3298 AN: 249414 AF XY: 0.00958

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.00694

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00425

GnomAD4 exome AF: 0.00524 AC: 7657 AN: 1460124 Hom.: 657 Cov.: 31 AF XY: 0.00441 AC XY: 3206 AN XY: 726438

African (AFR) AF: 0.189 AC: 6335 AN: 33462

American (AMR) AF: 0.00816 AC: 365 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.000325 AC: 28 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51962

Middle Eastern (MID) AF: 0.00833 AC: 48 AN: 5764

European-Non Finnish (NFE) AF: 0.000189 AC: 210 AN: 1111838

Other (OTH) AF: 0.0111 AC: 671 AN: 60368

GnomAD4 genome AF: 0.0525 AC: 7997 AN: 152246 Hom.: 726 Cov.: 32 AF XY: 0.0512 AC XY: 3808 AN XY: 74446

African (AFR) AF: 0.183 AC: 7607 AN: 41524

American (AMR) AF: 0.0163 AC: 249 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68024

Other (OTH) AF: 0.0464 AC: 98 AN: 2112

Alfa AF: 0.0281 Hom.: 90

Bravo AF: 0.0599

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.8
DANN	Benign	0.75
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4081614; hg19: chr19-4154846;