Genetic Variant CER1:p.Ala65Gly (chr9-14722479-G-C) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_005454.3(CER1):c.194C>G(p.Ala65Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,613,888 control chromosomes in the GnomAD database, including 101,211 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.43 ( 17446 hom., cov: 32)

Exomes 𝑓: 0.33 ( 83765 hom. )

Consequence

CER1
NM_005454.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.121

Publications

33 publications found

Variant links:

Genes affected

CER1 (HGNC:1862): (cerberus 1, DAN family BMP antagonist) This gene encodes a cytokine member of the cysteine knot superfamily, characterized by nine conserved cysteines and a cysteine knot region. The cerberus-related cytokines, together with Dan and DRM/Gremlin, represent a group of bone morphogenetic protein (BMP) antagonists that can bind directly to BMPs and inhibit their activity. [provided by RefSeq, Jul 2008]

CER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=1.5569218E-6).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.745 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CER1	NM_005454.3 link	c.194C>G	p.Ala65Gly	missense_variant	Exon 1 of 2	ENST00000380911.4	NP_005445.1	O95813
CER1	XR_001746419.2 link	n.255C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CER1	ENST00000380911.4 link	c.194C>G	p.Ala65Gly	missense_variant	Exon 1 of 2	1	NM_005454.3	ENSP00000370297.3		O95813

Frequencies

GnomAD3 genomes

AF:

0.433

AC:

65769

AN:

151938

Hom.:

17417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.753

Gnomad AMI

AF:

0.180

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0888

Gnomad SAS

AF:

0.315

Gnomad FIN

AF:

0.374

Gnomad MID

AF:

0.304

Gnomad NFE

AF:

0.318

Gnomad OTH

AF:

0.392

GnomAD2 exomes

AF:

0.330

AC:

82875

AN:

251410

AF XY:

0.323

show subpopulations

Gnomad AFR exome

AF:

0.764

Gnomad AMR exome

AF:

0.309

Gnomad ASJ exome

AF:

0.229

Gnomad EAS exome

AF:

0.0923

Gnomad FIN exome

AF:

0.358

Gnomad NFE exome

AF:

0.317

Gnomad OTH exome

AF:

0.318

GnomAD4 exome

AF:

0.326

AC:

477165

AN:

1461832

Hom.:

83765

Cov.:

AF XY:

0.325

AC XY:

236009

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.769

AC:

25759

AN:

33480

American (AMR)

AF:

0.311

AC:

13889

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.225

AC:

5891

AN:

26134

East Asian (EAS)

AF:

0.0689

AC:

2736

AN:

39700

South Asian (SAS)

AF:

0.332

AC:

28644

AN:

86258

European-Finnish (FIN)

AF:

0.355

AC:

18932

AN:

53396

Middle Eastern (MID)

AF:

0.294

AC:

1698

AN:

5766

European-Non Finnish (NFE)

AF:

0.323

AC:

359668

AN:

1111982

Other (OTH)

AF:

0.330

AC:

19948

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

19432

38865

58297

77730

97162

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11822

23644

35466

47288

59110

<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:

0.433

AC:

65850

AN:

152056

Hom.:

17446

Cov.:

AF XY:

0.430

AC XY:

31990

AN XY:

74316

show subpopulations

African (AFR)

AF:

0.752

AC:

31206

AN:

41474

American (AMR)

AF:

0.342

AC:

5222

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

767

AN:

3472

East Asian (EAS)

AF:

0.0884

AC:

457

AN:

5168

South Asian (SAS)

AF:

0.315

AC:

1516

AN:

4806

European-Finnish (FIN)

AF:

0.374

AC:

3950

AN:

10568

Middle Eastern (MID)

AF:

0.323

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.319

AC:

21653

AN:

67974

Other (OTH)

AF:

0.389

AC:

820

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1612

3224

4836

6448

8060

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

556

1112

1668

2224

2780

<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:

0.295

Hom.:

5436

Bravo

AF:

0.441

TwinsUK

AF:

0.322

AC:

1195

ALSPAC

AF:

0.320

AC:

1232

ESP6500AA

AF:

0.743

AC:

3273

ESP6500EA

AF:

0.328

AC:

2822

ExAC

AF:

0.339

AC:

41137

Asia WGS

AF:

0.238

AC:

833

AN:

3478

EpiCase

AF:

0.311

EpiControl

AF:

0.307

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.049

BayesDel_addAF

Benign

-0.83

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.8

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.083

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.0040

LIST_S2

Benign

0.14

MetaRNN

Benign

0.0000016

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-2.3

PhyloP100

0.12

PrimateAI

Benign

0.37

PROVEAN

Benign

0.70

REVEL

Benign

0.053

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.040

MPC

0.0066

ClinPred

0.0023

GERP RS

2.1

PromoterAI

-0.0026

Neutral

(source)

Varity_R

0.023

gMVP

0.13

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