Genetic Variant PCYT1B:p.Glu25Lys (chrX-24647033-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_004845.5(PCYT1B):c.73G>A(p.Glu25Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,209,228 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

PCYT1B
NM_004845.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

PCYT1B (HGNC:8755): (phosphate cytidylyltransferase 1B, choline) The protein encoded by this gene belongs to the cytidylyltransferase family. It is involved in the regulation of phosphatidylcholine biosynthesis. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

PCYT1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.036830366).

BS2

High Hemizygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYT1B	NM_004845.5 link	c.73G>A	p.Glu25Lys	missense_variant	Exon 1 of 8	ENST00000379144.7	NP_004836.2	Q9Y5K3-1
PCYT1B	NM_001163265.2 link	c.73G>A	p.Glu25Lys	missense_variant	Exon 1 of 9		NP_001156737.1	Q9Y5K3-2
PCYT1B	XM_017029977.2 link	c.-336G>A		5_prime_UTR_variant	Exon 1 of 9		XP_016885466.1
PCYT1B	NM_001163264.2 link	c.63+25537G>A		intron_variant	Intron 1 of 7		NP_001156736.1	Q9Y5K3-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCYT1B	ENST00000379144.7 link	c.73G>A	p.Glu25Lys	missense_variant	Exon 1 of 8	1	NM_004845.5	ENSP00000368439.2		Q9Y5K3-1

Frequencies

GnomAD3 genomes

AF:

0.0000625

AC:

AN:

111919

Hom.:

Cov.:

AF XY:

0.0000880

AC XY:

AN XY:

34083

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000665

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:

0.00000546

AC:

AN:

183313

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

67753

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000365

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:

0.00000456

AC:

AN:

1097255

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362621

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000114

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:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.0000625

AC:

AN:

111973

Hom.:

Cov.:

AF XY:

0.0000879

AC XY:

AN XY:

34147

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000665

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

Bravo

AF:

0.000125

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.73G>A (p.E25K) alteration is located in exon 1 (coding exon 1) of the PCYT1B gene. This alteration results from a G to A substitution at nucleotide position 73, causing the glutamic acid (E) at amino acid position 25 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.085

.;T

FATHMM_MKL

Benign

0.55

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0023

MetaRNN

Benign

0.037

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.29

N;N

REVEL

Benign

0.11

Sift

Benign

0.12

T;T

Sift4G

Benign

0.87

T;T

Polyphen

0.0

B;B

Vest4

0.23

MutPred

0.23

Gain of ubiquitination at E25 (P = 0);Gain of ubiquitination at E25 (P = 0);

MVP

0.25

MPC

0.0027

ClinPred

0.17

GERP RS

4.9

Varity_R

0.19

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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