3-196707578-C-T

Position:

chr3-196707578-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032898.5(CEP19):c.465G>A(p.Trp155*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,611,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CEP19
NM_032898.5 stop_gained

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.26

Variant links:

Genes affected

CEP19 (HGNC:28209): (centrosomal protein 19) The protein encoded by this gene localizes to centrosomes and primary cilia and co-localizes with a marker for the mother centriole. This gene resides in a region of human chromosome 3 that is linked to morbid obesity. A homozygous knockout of the orthologous gene in mouse resulted in mice with morbid obesity, hyperphagy, glucose intolerance, and insulin resistance. Mutations in this gene cause morbid obesity and spermatogenic failure (MOSPGF). This gene has a pseudogene on human chromosome 2. [provided by RefSeq, Apr 2014]

CEP19 links:

PIGX (HGNC:26046): (phosphatidylinositol glycan anchor biosynthesis class X) This gene encodes a type I transmembrane protein in the endoplasmic reticulum (ER). The protein is an essential component of glycosylphosphatidylinositol-mannosyltransferase I, which transfers the first of the four mannoses in the GPI-anchor precursors during GPI-anchor biosynthesis. Studies in rat indicate that the protein is translated from a non-AUG translation initiation site. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

PIGX links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP19	NM_032898.5 linkuse as main transcript	c.465G>A	p.Trp155*	stop_gained	3/3	ENST00000409690.5	NP_116287.3	Q96LK0
CEP19	NM_001379469.1 linkuse as main transcript	c.465G>A	p.Trp155*	stop_gained	3/3		NP_001366398.1
CEP19	NM_001379470.1 linkuse as main transcript	c.465G>A	p.Trp155*	stop_gained	3/3		NP_001366399.1
CEP19	NM_001379468.1 linkuse as main transcript	c.360G>A	p.Trp120*	stop_gained	2/2		NP_001366397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CEP19	ENST00000409690.5 linkuse as main transcript	c.465G>A	p.Trp155*	stop_gained	3/3	1	NM_032898.5	ENSP00000387209.4	Q96LK0
CEP19	ENST00000399942.4 linkuse as main transcript	c.360G>A	p.Trp120*	stop_gained	2/2	5		ENSP00000382823.4	A8MX07
PIGX	ENST00000426755.5 linkuse as main transcript	c.-11-9280C>T		intron_variant		3		ENSP00000409073.1	C9JLT7

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000161

AC:

AN:

247940

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134620

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459148

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725872

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000897

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000165

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 27, 2022

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. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1348086). This variant has not been reported in the literature in individuals affected with CEP19-related conditions. This variant is present in population databases (rs766053526, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Trp159*) in the CEP19 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the CEP19 protein. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.66

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.99

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.98

Vest4

0.30

GERP RS

5.7

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