9-14722479-G-C

Position:

• chr9-14722479-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (17446 hom., cov: 32)
  • Exomes 𝑓: 0.33 (83765 hom.)
• Consequence: CER1 NM_005454.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.121

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	Protein	UniProt
CER1	NM_005454.3	c.194C>G	p.Ala65Gly	missense_variant	1/2	ENST00000380911.4	NP_005445.1
CER1	XR_001746419.2	n.255C>G		non_coding_transcript_exon_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CER1	ENST00000380911.4	c.194C>G	p.Ala65Gly	missense_variant	1/2	1	NM_005454.3	ENSP00000370297.3

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65769 AN: 151938 Hom.: 17417 Cov.: 32

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

GnomAD3 exomes AF: 0.330 AC: 82875 AN: 251410 Hom.: 16026 AF XY: 0.323 AC XY: 43841 AN XY: 135878

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 SAS exome AF: 0.328

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.: 45 AF XY: 0.325 AC XY: 236009 AN XY: 727222

Gnomad4 AFR exome AF: 0.769

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.0689

Gnomad4 SAS exome AF: 0.332

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.323

Gnomad4 OTH exome AF: 0.330

GnomAD4 genome AF: 0.433 AC: 65850 AN: 152056 Hom.: 17446 Cov.: 32 AF XY: 0.430 AC XY: 31990 AN XY: 74316

Gnomad4 AFR AF: 0.752

Gnomad4 AMR AF: 0.342

Gnomad4 ASJ AF: 0.221

Gnomad4 EAS AF: 0.0884

Gnomad4 SAS AF: 0.315

Gnomad4 FIN AF: 0.374

Gnomad4 NFE AF: 0.319

Gnomad4 OTH AF: 0.389

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	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.8
DANN	Benign	0.40
DEOGEN2	Benign	0.083	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	0.0000016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.3	N
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.70	N
REVEL	Benign	0.053
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.0066
ClinPred		0.0023	T
GERP RS		2.1
Varity_R		0.023
gMVP		0.13

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: rs3747532; hg19: chr9-14722477; COSMIC: COSV66603074;