chr11-46300068-C-T

Position:

chr11-46300068-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_052854.4(CREB3L1):c.236C>T(p.Thr79Met) variant causes a missense change. The variant allele was found at a frequency of 0.000184 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

CREB3L1
NM_052854.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.60

Variant links:

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]

CREB3L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.02505207).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CREB3L1	NM_052854.4 linkuse as main transcript	c.236C>T	p.Thr79Met	missense_variant	2/12	ENST00000621158.5
CREB3L1	XM_006718380.4 linkuse as main transcript	c.236C>T	p.Thr79Met	missense_variant	2/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB3L1	ENST00000621158.5 linkuse as main transcript	c.236C>T	p.Thr79Met	missense_variant	2/12	1	NM_052854.4	P1	Q96BA8-1
CREB3L1	ENST00000534787.1 linkuse as main transcript	c.98C>T	p.Thr33Met	missense_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000325

AC:

AN:

248920

Hom.:

AF XY:

0.000392

AC XY:

AN XY:

135078

show subpopulations

Gnomad AFR exome

AF:

0.0000647

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00137

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000222

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000187

AC:

273

AN:

1461630

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

170

AN XY:

727092

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00175

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000765

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000158

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000228

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00104

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000114

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.000355

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.236C>T (p.T79M) alteration is located in exon 2 (coding exon 2) of the CREB3L1 gene. This alteration results from a C to T substitution at nucleotide position 236, causing the threonine (T) at amino acid position 79 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 79 of the CREB3L1 protein (p.Thr79Met). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CREB3L1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1417122). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.33

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.0090

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.36

Sift4G

Benign

0.066

T;T

Polyphen

0.048

B;.

Vest4

0.32

MVP

0.48

ClinPred

0.073

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.033

gMVP

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over