rs4873

Variant names:

• chr5-90407824-C-G
• rs4873
• NM_004365.4:c.28G>C

Variant summary

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

The NM_004365.4(CETN3):​c.28G>C​(p.Val10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 1,581,828 control chromosomes in the GnomAD database, including 53,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.20 (3521 hom., cov: 32)
  • Exomes 𝑓: 0.26 (49486 hom.)
• Consequence: CETN3 NM_004365.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08

Genes affected

CETN3 (HGNC:1868): (centrin 3) The protein encoded by this gene contains four EF-hand calcium binding domains, and is a member of the centrin protein family. Centrins are evolutionarily conserved proteins similar to the CDC31 protein of S. cerevisiae. Yeast CDC31 is located at the centrosome of interphase and mitotic cells, where it plays a fundamental role in centrosome duplication and separation. Multiple forms of the proteins similar to the yeast centrin have been identified in human and other mammalian cells, some of which have been shown to be associated with centrosome fractions. This protein appears to be one of the most abundant centrins associated with centrosome, which suggests a similar function to its yeast counterpart. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001967162).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CETN3	NM_004365.4	c.28G>C	p.Val10Leu	missense_variant	Exon 2 of 5	ENST00000283122.8	NP_004356.2
CETN3	NM_001297765.2	c.28G>C	p.Val10Leu	missense_variant	Exon 2 of 6		NP_001284694.1
CETN3	NM_001297768.2	c.28G>C	p.Val10Leu	missense_variant	Exon 2 of 6		NP_001284697.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CETN3	ENST00000283122.8	c.28G>C	p.Val10Leu	missense_variant	Exon 2 of 5	1	NM_004365.4	ENSP00000283122.3

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30243 AN: 151928 Hom.: 3517 Cov.: 32

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.177

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.223

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.183

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.267

Gnomad OTH AF: 0.202

GnomAD3 exomes AF: 0.225 AC: 52034 AN: 231506 Hom.: 6256 AF XY: 0.232 AC XY: 29077 AN XY: 125446

Gnomad AFR exome AF: 0.0850

Gnomad AMR exome AF: 0.148

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.238

Gnomad SAS exome AF: 0.266

Gnomad FIN exome AF: 0.183

Gnomad NFE exome AF: 0.261

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.258 AC: 369211 AN: 1429782 Hom.: 49486 Cov.: 30 AF XY: 0.259 AC XY: 184408 AN XY: 710814

Gnomad4 AFR exome AF: 0.0798

Gnomad4 AMR exome AF: 0.151

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.204

Gnomad4 SAS exome AF: 0.264

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.274

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.199 AC: 30240 AN: 152046 Hom.: 3521 Cov.: 32 AF XY: 0.195 AC XY: 14468 AN XY: 74330

Gnomad4 AFR AF: 0.0856

Gnomad4 AMR AF: 0.177

Gnomad4 ASJ AF: 0.219

Gnomad4 EAS AF: 0.221

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.183

Gnomad4 NFE AF: 0.267

Gnomad4 OTH AF: 0.199

Alfa AF: 0.250 Hom.: 3763

Bravo AF: 0.191

TwinsUK AF: 0.284 AC: 1054

ALSPAC AF: 0.275 AC: 1060

ESP6500AA AF: 0.0936 AC: 412

ESP6500EA AF: 0.269 AC: 2314

ExAC AF: 0.228 AC: 27707

Asia WGS AF: 0.209 AC: 724 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0097	T;.;.;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T;T;T;T
MetaRNN	Benign	0.0020	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N;.;.;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.43	N;N;N;N;N
REVEL	Benign	0.092
Sift	Benign	0.33	T;T;T;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.15
MutPred		0.062		Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MPC		0.19
ClinPred		0.0040	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.053
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs4873; hg19: chr5-89703641; COSMIC: COSV51617006; COSMIC: COSV51617006;