11-46278143-A-G

Variant names:

• chr11-46278143-A-G
• rs1052140211
• NM_052854.4:c.32A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_052854.4(CREB3L1):​c.32A>G​(p.Asp11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000127 in 1,415,368 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CREB3L1 NM_052854.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.03

Genes affected

CREB3L1 (HGNC:18856): (cAMP responsive element binding protein 3 like 1) The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER). However, upon stress to the ER, the encoded protein is cleaved and the released cytoplasmic transcription factor domain translocates to the nucleus. There it activates the transcription of target genes by binding to box-B elements. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17089939).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB3L1	NM_052854.4	c.32A>G	p.Asp11Gly	missense_variant	Exon 1 of 12	ENST00000621158.5	NP_443086.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB3L1	ENST00000621158.5	c.32A>G	p.Asp11Gly	missense_variant	Exon 1 of 12	1	NM_052854.4	ENSP00000481956.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000127 AC: 18 AN: 1415368 Hom.: 0 Cov.: 31 AF XY: 0.0000129 AC XY: 9 AN XY: 700022

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000147

Gnomad4 OTH exome AF: 0.0000341

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.32A>G (p.D11G) alteration is located in exon 1 (coding exon 1) of the CREB3L1 gene. This alteration results from a A to G substitution at nucleotide position 32, causing the aspartic acid (D) at amino acid position 11 to be replaced by a glycine (G). 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	0.29
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.024
Eigen_PC	Benign	0.067
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Pathogenic	0.84	D
Sift4G	Uncertain	0.029	D
Polyphen		0.42	B
Vest4		0.22
MutPred		0.21		Loss of stability (P = 0.031);
MVP		0.51
ClinPred		0.93	D
GERP RS		3.5
Varity_R		0.29
gMVP		0.23

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: rs1052140211; hg19: chr11-46299694;