3-196707673-A-G

Position:

chr3-196707673-A-G

Variant summary

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

The NM_032898.5(CEP19):c.370T>C(p.Phe124Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CEP19
NM_032898.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.58

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:

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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
CEP19	NM_032898.5 linkuse as main transcript	c.370T>C	p.Phe124Leu	missense_variant	3/3	ENST00000409690.5	NP_116287.3
CEP19	NM_001379469.1 linkuse as main transcript	c.370T>C	p.Phe124Leu	missense_variant	3/3		NP_001366398.1
CEP19	NM_001379470.1 linkuse as main transcript	c.370T>C	p.Phe124Leu	missense_variant	3/3		NP_001366399.1
CEP19	NM_001379468.1 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	2/2		NP_001366397.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
CEP19	ENST00000409690.5 linkuse as main transcript	c.370T>C	p.Phe124Leu	missense_variant	3/3	1	NM_032898.5	ENSP00000387209	P1
CEP19	ENST00000399942.4 linkuse as main transcript	c.265T>C	p.Phe89Leu	missense_variant	2/2	5		ENSP00000382823
PIGX	ENST00000426755.5 linkuse as main transcript	c.-11-9185A>G		intron_variant		3		ENSP00000409073

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000401

AC:

AN:

249538

Hom.:

AF XY:

0.00000739

AC XY:

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000827

AC:

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

Nov 08, 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with CEP19-related conditions. This variant is present in population databases (rs527513703, gnomAD 0.003%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 128 of the CEP19 protein (p.Phe128Leu). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.015

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Uncertain

-0.072

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.4

D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0050

D;D

Sift4G

Uncertain

0.013

D;D

Vest4

0.74

MVP

0.75

MPC

0.44

ClinPred

0.96

GERP RS

5.7

gMVP

0.58

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