NM_001312673.2:c.968dupG

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 5P and 1B. PVS1_StrongPP5BS1_Supporting

The NM_001312673.2(PCYT1A):c.968dupG(p.Ser323ArgfsTer38) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000828 in 1,569,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S323S) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

PCYT1A
NM_001312673.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.54

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

cholestasis, progressive familial intrahepatic, 6
Inheritance: AR, Unknown Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

SLC51A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 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 0.123 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PP5

Variant 3-196238823-G-GC is Pathogenic according to our data. Variant chr3-196238823-G-GC is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 101065.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000394 (6/152180) while in subpopulation AFR AF = 0.000145 (6/41444). AF 95% confidence interval is 0.0000628. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001312673.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCYT1A	NM_001312673.2	MANE Select	c.968dupG	p.Ser323ArgfsTer38	frameshift	Exon 9 of 9	NP_001299602.1	P49585
	PCYT1A	NM_005017.4		c.968dupG	p.Ser323ArgfsTer38	frameshift	Exon 10 of 10	NP_005008.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PCYT1A	ENST00000431016.6	TSL:1 MANE Select	c.968dupG	p.Ser323ArgfsTer38	frameshift	Exon 9 of 9	ENSP00000394617.1	P49585
PCYT1A	ENST00000292823.6	TSL:1	c.968dupG	p.Ser323ArgfsTer38	frameshift	Exon 10 of 10	ENSP00000292823.2	P49585
PCYT1A	ENST00000419333.5	TSL:5	c.968dupG	p.Ser323ArgfsTer38	frameshift	Exon 8 of 9	ENSP00000390968.1	C9JEJ2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000477

AC:

AN:

209704

AF XY:

0.00000879

show subpopulations

Gnomad AFR exome

AF:

0.0000735

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.00000494

AC:

AN:

1417434

Hom.:

Cov.:

AF XY:

0.00000568

AC XY:

AN XY:

703690

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

31148

American (AMR)

AF:

0.0000258

AC:

AN:

38740

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24582

East Asian (EAS)

AF:

0.00

AC:

AN:

35898

South Asian (SAS)

AF:

0.00

AC:

AN:

79906

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52662

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5194

European-Non Finnish (NFE)

AF:

0.00000183

AC:

AN:

1090700

Other (OTH)

AF:

0.0000171

AC:

AN:

58604

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.561

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000642

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

7.5

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over