NM_014679.5:c.572T>A

Variant names:

• chr11-95817854-T-A
• rs150399616
• NM_014679.5:c.572T>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS1

The NM_014679.5(CEP57):​c.572T>A​(p.Leu191His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0007 in 1,613,964 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00046 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (1 hom.)
• Consequence: CEP57 NM_014679.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 2.57
• Publications: 4 publications found

Genes affected

CEP57 (HGNC:30794): (centrosomal protein 57) This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]

CEP57 Gene-Disease associations (from GenCC):

• mosaic variegated aneuploidy syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• mosaic variegated aneuploidy syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021930486).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00046 (70/152284) while in subpopulation NFE AF = 0.000823 (56/68024). AF 95% confidence interval is 0.000651. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014679.5. 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
	CEP57	NM_014679.5	MANE Select	c.572T>A	p.Leu191His	missense	Exon 5 of 11	NP_055494.2
	CEP57	NM_001243776.2		c.545T>A	p.Leu182His	missense	Exon 6 of 12	NP_001230705.1	Q86XR8-5
	CEP57	NM_001243777.2		c.572T>A	p.Leu191His	missense	Exon 5 of 10	NP_001230706.1	Q86XR8-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP57	ENST00000325542.10	TSL:1 MANE Select	c.572T>A	p.Leu191His	missense	Exon 5 of 11	ENSP00000317902.5	Q86XR8-1
	CEP57	ENST00000325486.9	TSL:1	c.572T>A	p.Leu191His	missense	Exon 5 of 10	ENSP00000317487.5	Q86XR8-2
	CEP57	ENST00000538658.5	TSL:1	c.572T>A	p.Leu191His	missense	Exon 5 of 7	ENSP00000445706.1	Q86XR8-3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000533 AC: 134 AN: 251426 AF XY: 0.000523

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00100

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000725 AC: 1059 AN: 1461680 Hom.: 1 Cov.: 30 AF XY: 0.000703 AC XY: 511 AN XY: 727142

African (AFR) AF: 0.000120 AC: 4 AN: 33472

American (AMR) AF: 0.000157 AC: 7 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39654

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.000917 AC: 1020 AN: 1111888

Other (OTH) AF: 0.000397 AC: 24 AN: 60382

GnomAD4 genome AF: 0.000460 AC: 70 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74466

African (AFR) AF: 0.000192 AC: 8 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000808 Hom.: 0

Bravo AF: 0.000582

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.000763

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Mosaic variegated aneuploidy syndrome 2 (4)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.39
CADD	Uncertain	23
DANN	Benign	0.91
DEOGEN2	Benign	0.034	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		2.6
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.12
Sift	Benign	0.44	T
Sift4G	Benign	0.59	T
Polyphen		0.0090	B
Vest4		0.37
MVP		0.36
MPC		0.44
ClinPred		0.023	T
GERP RS		4.2
PromoterAI		0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.17
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs150399616; hg19: chr11-95551018; COSMIC: COSV99051099; COSMIC: COSV99051099;