chr5-90407824-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 14/21 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 0.20 (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
• Publications: 27 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004365.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETN3	NM_004365.4	MANE Select	c.28G>C	p.Val10Leu	missense	Exon 2 of 5	NP_004356.2
	CETN3	NM_001297765.2		c.28G>C	p.Val10Leu	missense	Exon 2 of 6	NP_001284694.1	E5RJF8
	CETN3	NM_001297768.2		c.28G>C	p.Val10Leu	missense	Exon 2 of 6	NP_001284697.1	E5RFM2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CETN3	ENST00000283122.8	TSL:1 MANE Select	c.28G>C	p.Val10Leu	missense	Exon 2 of 5	ENSP00000283122.3	O15182
	CETN3	ENST00000919890.1		c.28G>C	p.Val10Leu	missense	Exon 2 of 6	ENSP00000589949.1
	CETN3	ENST00000522083.5	TSL:2	c.28G>C	p.Val10Leu	missense	Exon 2 of 6	ENSP00000428259.1	E5RJF8

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

GnomAD2 exomes AF: 0.225 AC: 52034 AN: 231506 AF XY: 0.232

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 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

African (AFR) AF: 0.0798 AC: 2572 AN: 32224

American (AMR) AF: 0.151 AC: 6116 AN: 40464

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5773 AN: 25390

East Asian (EAS) AF: 0.204 AC: 7859 AN: 38496

South Asian (SAS) AF: 0.264 AC: 21070 AN: 79784

European-Finnish (FIN) AF: 0.186 AC: 9787 AN: 52576

Middle Eastern (MID) AF: 0.241 AC: 1369 AN: 5688

European-Non Finnish (NFE) AF: 0.274 AC: 300082 AN: 1096130

Other (OTH) AF: 0.247 AC: 14583 AN: 59030

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

African (AFR) AF: 0.0856 AC: 3555 AN: 41520

American (AMR) AF: 0.177 AC: 2700 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 758 AN: 3468

East Asian (EAS) AF: 0.221 AC: 1147 AN: 5182

South Asian (SAS) AF: 0.271 AC: 1307 AN: 4822

European-Finnish (FIN) AF: 0.183 AC: 1927 AN: 10556

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.267 AC: 18109 AN: 67894

Other (OTH) AF: 0.199 AC: 420 AN: 2106

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 v4.9

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
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.092
Sift	Benign	0.33	T
Sift4G	Benign	0.34	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.062		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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4873; hg19: chr5-89703641; COSMIC: COSV51617006; COSMIC: COSV51617006;