3-196707860-G-GT

Variant names:

• chr3-196707860-G-GT
• rs1553794304
• NM_032898.5:c.182dupA

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_032898.5(CEP19):​c.182dupA​(p.Tyr61fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CEP19 NM_032898.5 frameshift, stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.62
• Publications: 0 publications found

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]

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.63 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-196707860-G-GT is Pathogenic according to our data. Variant chr3-196707860-G-GT is described in ClinVar as Pathogenic. ClinVar VariationId is 430642.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032898.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP19	NM_032898.5	MANE Select	c.182dupA	p.Tyr61fs	frameshift stop_gained	Exon 3 of 3	NP_116287.3
	CEP19	NM_001379469.1		c.182dupA	p.Tyr61fs	frameshift stop_gained	Exon 3 of 3	NP_001366398.1
	CEP19	NM_001379470.1		c.182dupA	p.Tyr61fs	frameshift stop_gained	Exon 3 of 3	NP_001366399.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP19	ENST00000409690.5	TSL:1 MANE Select	c.182dupA	p.Tyr61fs	frameshift stop_gained	Exon 3 of 3	ENSP00000387209.4
	CEP19	ENST00000399942.4	TSL:5	c.77dupA	p.Tyr26fs	frameshift stop_gained	Exon 2 of 2	ENSP00000382823.4
	PIGX	ENST00000426755.5	TSL:3	c.-11-8997dupT		intron	N/A	ENSP00000409073.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Bardet-Biedl syndrome Pathogenic:1

Jul 05, 2017

Tolun Lab, Human Genetics Laboratory, Bogazici University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

it is predicted as truncating, but no further studies were performed.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6
Mutation Taster		=2/198	disease causing (ClinVar)

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: rs1553794304; hg19: chr3-196434731;