chr19-4170001-G-A

Variant names:

• chr19-4170001-G-A
• rs350852
• NM_032607.3:c.822-139G>A

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.822-139G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.873 in 819,526 control chromosomes in the GnomAD database, including 314,080 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (59958 hom., cov: 32)
  • Exomes 𝑓: 0.87 (254122 hom.)
• Consequence: CREB3L3 NM_032607.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.743
• Publications: 16 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=-0.89).
• BP6: Variant 19-4170001-G-A is Benign according to our data. Variant chr19-4170001-G-A is described in ClinVar as Benign. ClinVar VariationId is 1239450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.948 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L3	NM_032607.3	MANE Select	c.822-139G>A		intron	N/A	NP_115996.1
	CREB3L3	NM_001271995.2		c.819-139G>A		intron	N/A	NP_001258924.1
	CREB3L3	NM_001271996.2		c.816-139G>A		intron	N/A	NP_001258925.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CREB3L3	ENST00000078445.7	TSL:1 MANE Select	c.822-139G>A		intron	N/A	ENSP00000078445.1
	CREB3L3	ENST00000595923.5	TSL:1	c.819-139G>A		intron	N/A	ENSP00000469355.1
	CREB3L3	ENST00000602257.5	TSL:1	c.816-139G>A		intron	N/A	ENSP00000472399.1

Frequencies

GnomAD3 genomes AF: 0.885 AC: 134509 AN: 152068 Hom.: 59900 Cov.: 32

Gnomad AFR AF: 0.955

Gnomad AMI AF: 0.829

Gnomad AMR AF: 0.778

Gnomad ASJ AF: 0.865

Gnomad EAS AF: 0.684

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.851

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.885

Gnomad OTH AF: 0.888

GnomAD4 exome AF: 0.870 AC: 580918 AN: 667340 Hom.: 254122 AF XY: 0.875 AC XY: 312837 AN XY: 357416

African (AFR) AF: 0.958 AC: 17257 AN: 18010

American (AMR) AF: 0.734 AC: 27410 AN: 37364

Ashkenazi Jewish (ASJ) AF: 0.864 AC: 17809 AN: 20604

East Asian (EAS) AF: 0.694 AC: 23440 AN: 33762

South Asian (SAS) AF: 0.923 AC: 62467 AN: 67698

European-Finnish (FIN) AF: 0.862 AC: 35995 AN: 41752

Middle Eastern (MID) AF: 0.937 AC: 2783 AN: 2970

European-Non Finnish (NFE) AF: 0.885 AC: 364019 AN: 411114

Other (OTH) AF: 0.873 AC: 29738 AN: 34066

GnomAD4 genome AF: 0.885 AC: 134627 AN: 152186 Hom.: 59958 Cov.: 32 AF XY: 0.879 AC XY: 65408 AN XY: 74400

African (AFR) AF: 0.955 AC: 39698 AN: 41552

American (AMR) AF: 0.777 AC: 11867 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.865 AC: 3000 AN: 3468

East Asian (EAS) AF: 0.686 AC: 3534 AN: 5154

South Asian (SAS) AF: 0.910 AC: 4391 AN: 4824

European-Finnish (FIN) AF: 0.851 AC: 9018 AN: 10598

Middle Eastern (MID) AF: 0.939 AC: 276 AN: 294

European-Non Finnish (NFE) AF: 0.885 AC: 60213 AN: 68008

Other (OTH) AF: 0.888 AC: 1874 AN: 2110

Alfa AF: 0.884 Hom.: 108259

Bravo AF: 0.883

Asia WGS AF: 0.817 AC: 2843 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

May 10, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.24
DANN	Benign	0.38
PhyloP100		-0.74
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs350852; hg19: chr19-4169998; COSMIC: COSV50288371; COSMIC: COSV50288371;