4-55981344-A-G

Position:

chr4-55981344-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_025009.5(CEP135):c.1744A>G(p.Met582Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,585,744 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 1 hom. )

Consequence

CEP135
NM_025009.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 3.06

Variant links:

Genes affected

CEP135 (HGNC:29086): (centrosomal protein 135) This gene encodes a centrosomal protein, which acts as a scaffolding protein during early centriole biogenesis, and is also required for centriole-centriole cohesion during interphase. Mutations in this gene are associated with autosomal recessive primary microcephaly-8. [provided by RefSeq, Jun 2012]

CEP135 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.050658077).

BP6

Variant 4-55981344-A-G is Benign according to our data. Variant chr4-55981344-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128695.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.00115 (1653/1433420) while in subpopulation NFE AF= 0.00147 (1626/1104096). AF 95% confidence interval is 0.00141. There are 1 homozygotes in gnomad4_exome. There are 816 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CEP135	NM_025009.5 linkuse as main transcript	c.1744A>G	p.Met582Val	missense_variant	13/26	ENST00000257287.5	NP_079285.2
CEP135	XM_006714055.4 linkuse as main transcript	c.1711A>G	p.Met571Val	missense_variant	13/26		XP_006714118.1
CEP135	XM_005265788.5 linkuse as main transcript	c.673A>G	p.Met225Val	missense_variant	6/19		XP_005265845.1
CEP135	XM_011534412.2 linkuse as main transcript	c.214A>G	p.Met72Val	missense_variant	3/16		XP_011532714.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP135	ENST00000257287.5 linkuse as main transcript	c.1744A>G	p.Met582Val	missense_variant	13/26	1	NM_025009.5	ENSP00000257287	P1	Q66GS9-1
CEP135	ENST00000506202.1 linkuse as main transcript	n.1694A>G		non_coding_transcript_exon_variant	6/19	1

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000617

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000266

AC:

AN:

222132

Hom.:

AF XY:

0.000299

AC XY:

AN XY:

120542

show subpopulations

Gnomad AFR exome

AF:

0.000135

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000539

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00115

AC:

1653

AN:

1433420

Hom.:

Cov.:

AF XY:

0.00115

AC XY:

816

AN XY:

712410

show subpopulations

Gnomad4 AFR exome

AF:

0.0000960

Gnomad4 AMR exome

AF:

0.0000273

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.00147

Gnomad4 OTH exome

AF:

0.000355

GnomAD4 genome

AF:

0.000322

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000617

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000575

Hom.:

Bravo

AF:

0.000310

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000198

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 23, 2022	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 582 of the CEP135 protein (p.Met582Val). This variant is present in population databases (rs144041768, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with CEP135-related conditions. ClinVar contains an entry for this variant (Variation ID: 128695). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 16, 2014	- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.010

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.019

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.65

M_CAP

Benign

0.0081

MetaRNN

Benign

0.051

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.21

REVEL

Benign

0.069

Sift

Benign

0.22

Sift4G

Benign

0.43

Polyphen

0.0

Vest4

0.18

MVP

0.51

MPC

0.059

ClinPred

0.074

GERP RS

4.7

Varity_R

0.11

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over