chr3-196238801-AG-A

Position:

chr3-196238801-AG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_001312673.2(PCYT1A):c.990del(p.Ser331ProfsTer166) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000689 in 1,580,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000072 ( 0 hom. )

Consequence

PCYT1A
NM_001312673.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: -0.272

Variant links:

Genes affected

PCYT1A (HGNC:8754): (phosphate cytidylyltransferase 1A, choline) This gene belongs to the cytidylyltransferase family and is involved in the regulation of phosphatidylcholine biosynthesis. Mutations in this gene are associated with spondylometaphyseal dysplasia with cone-rod dystrophy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

PCYT1A links:

SLC51A (HGNC:29955): (solute carrier family 51 member A) Predicted to enable protein heterodimerization activity; protein homodimerization activity; and transmembrane transporter activity. Involved in bile acid secretion. Located in basolateral plasma membrane. Implicated in progressive familial intrahepatic cholestasis. [provided by Alliance of Genome Resources, Apr 2022]

SLC51A links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 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 0.103 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-196238801-AG-A is Pathogenic according to our data. Variant chr3-196238801-AG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 101061.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr3-196238801-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCYT1A	NM_001312673.2 linkuse as main transcript	c.990del	p.Ser331ProfsTer166	frameshift_variant	9/9	ENST00000431016.6	NP_001299602.1
PCYT1A	NM_005017.4 linkuse as main transcript	c.990del	p.Ser331ProfsTer166	frameshift_variant	10/10		NP_005008.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCYT1A	ENST00000431016.6 linkuse as main transcript	c.990del	p.Ser331ProfsTer166	frameshift_variant	9/9	1	NM_001312673.2	ENSP00000394617	P1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

151912

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:

0.0000588

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000765

AC:

AN:

222150

Hom.:

AF XY:

0.0000910

AC XY:

AN XY:

120944

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000342

Gnomad ASJ exome

AF:

0.000217

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000378

Gnomad FIN exome

AF:

0.000142

Gnomad NFE exome

AF:

0.0000973

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000721

AC:

103

AN:

1429024

Hom.:

Cov.:

AF XY:

0.0000802

AC XY:

AN XY:

710552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.0000497

Gnomad4 ASJ exome

AF:

0.0000790

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000159

Gnomad4 FIN exome

AF:

0.000151

Gnomad4 NFE exome

AF:

0.0000675

Gnomad4 OTH exome

AF:

0.0000508

GnomAD4 genome

AF:

0.0000395

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.000480

Bravo

AF:

0.0000642

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Aug 28, 2019	A heterozygous deletion variant was identified, NM_005017.3(PCYT1A):c.990delC in exon 10 of 10 of the PCYT1A gene. This deletion is predicted to cause a frameshift starting at position 331, introducing a stop codon 165 residues downstream, NP_005008.2(PCYT1A):p.(Ser331Profs*166). The variant is predicted to result in a loss of normal protein function through an extension of the reading frame, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD population database at a frequency of 0.007% (19 heterozygotes, 0 homozygotes). It has been previously reported in patients with Spondylometaphyseal dysplasia with cone-rod dystrophy (ClinVar, Hoover-Fong, J. et al. (2014)). Other variants predicted to cause an extension of the reading frame have been reported as pathogenic in individuals with this condition (Payne, F. et al (2014)). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -
Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 02, 2014	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 10, 2023

This sequence change results in a frameshift in the PCYT1A gene (p.Ser331Profs*166). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the PCYT1A protein and extend the protein by 128 additional amino acid residues. This variant is present in population databases (rs587777193, gnomAD 0.02%). This frameshift has been observed in individual(s) with spondylometaphyseal dysplasia with cone-rod dystrophy (PMID: 24387990). ClinVar contains an entry for this variant (Variation ID: 101061). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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