Genetic Variant NM_001255978.2:c.283C>T (chr1-153969038-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001255978.2(CREB3L4):c.283C>T(p.Pro95Ser) variant causes a missense change. The variant allele was found at a frequency of 0.294 in 1,613,738 control chromosomes in the GnomAD database, including 71,770 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.26 ( 5747 hom., cov: 32)

Exomes 𝑓: 0.30 ( 66023 hom. )

Consequence

CREB3L4
NM_001255978.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.60

Publications

51 publications found

Variant links:

Genes affected

CREB3L4 (HGNC:18854): (cAMP responsive element binding protein 3 like 4) This gene encodes a CREB (cAMP responsive element binding) protein with a transmembrane domain which localizes it to the ER membrane. The encoded protein is a transcriptional activator which contains a dimerization domain, and this protein may function in a number of processing pathways including protein processing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

CREB3L4 links:

ENSG00000285779 (HGNC:):

ENSG00000285779 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032182932).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.374 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREB3L4	NM_001255978.2 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 3 of 10	ENST00000368607.8	NP_001242907.1	Q8TEY5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREB3L4	ENST00000368607.8 link	c.283C>T	p.Pro95Ser	missense_variant	Exon 3 of 10	1	NM_001255978.2	ENSP00000357596.3		Q8TEY5-1
ENSG00000285779	ENST00000648921.1 link	n.193-5335G>A		intron_variant	Intron 2 of 5			ENSP00000498105.1		A0A3B3ITX8

Frequencies

GnomAD3 genomes

AF:

0.261

AC:

39628

AN:

151982

Hom.:

5747

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.382

Gnomad ASJ

AF:

0.299

Gnomad EAS

AF:

0.282

Gnomad SAS

AF:

0.320

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.307

Gnomad NFE

AF:

0.296

Gnomad OTH

AF:

0.289

GnomAD2 exomes

AF:

0.314

AC:

78884

AN:

251440

AF XY:

0.315

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.432

Gnomad ASJ exome

AF:

0.316

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.332

Gnomad NFE exome

AF:

0.307

Gnomad OTH exome

AF:

0.330

GnomAD4 exome

AF:

0.297

AC:

434702

AN:

1461638

Hom.:

66023

Cov.:

AF XY:

0.299

AC XY:

217403

AN XY:

727140

show subpopulations

African (AFR)

AF:

0.118

AC:

3966

AN:

33478

American (AMR)

AF:

0.427

AC:

19096

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

8054

AN:

26134

East Asian (EAS)

AF:

0.301

AC:

11948

AN:

39698

South Asian (SAS)

AF:

0.315

AC:

27155

AN:

86254

European-Finnish (FIN)

AF:

0.337

AC:

18017

AN:

53416

Middle Eastern (MID)

AF:

0.342

AC:

1972

AN:

5768

European-Non Finnish (NFE)

AF:

0.294

AC:

327023

AN:

1111782

Other (OTH)

AF:

0.289

AC:

17471

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

17812

35625

53437

71250

89062

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10714

21428

32142

42856

53570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.261

AC:

39643

AN:

152100

Hom.:

5747

Cov.:

AF XY:

0.266

AC XY:

19788

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.125

AC:

5188

AN:

41510

American (AMR)

AF:

0.383

AC:

5840

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.299

AC:

1038

AN:

3468

East Asian (EAS)

AF:

0.283

AC:

1462

AN:

5168

South Asian (SAS)

AF:

0.320

AC:

1541

AN:

4816

European-Finnish (FIN)

AF:

0.337

AC:

3569

AN:

10584

Middle Eastern (MID)

AF:

0.306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.296

AC:

20101

AN:

67974

Other (OTH)

AF:

0.287

AC:

605

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1455

2910

4365

5820

7275

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

412

824

1236

1648

2060

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.286

Hom.:

30606

Bravo

AF:

0.261

TwinsUK

AF:

0.300

AC:

1113

ALSPAC

AF:

0.284

AC:

1096

ESP6500AA

AF:

0.123

AC:

544

ESP6500EA

AF:

0.283

AC:

2436

ExAC

AF:

0.308

AC:

37341

Asia WGS

AF:

0.277

AC:

964

AN:

3478

EpiCase

AF:

0.308

EpiControl

AF:

0.317

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

T;T;T;.;T;.;T

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.82

T;.;.;T;D;T;T

MetaRNN

Benign

0.0032

T;T;T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Uncertain

2.5

.;M;M;.;M;.;.

PhyloP100

4.6

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-4.1

D;D;D;D;D;D;D

REVEL

Benign

0.12

Sift

Benign

0.053

T;D;D;D;D;D;D

Sift4G

Uncertain

0.051

T;T;T;D;T;T;D

Polyphen

0.99

.;D;D;.;D;.;.

Vest4

0.17, 0.16, 0.43, 0.16, 0.34

MPC

0.23

ClinPred

0.021

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.36

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over