Genetic Variant PCYT1B:p.Glu21Lys (chrX-24647045-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004845.5(PCYT1B):c.61G>A(p.Glu21Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000207 in 1,209,119 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 3 hem. )

Consequence

PCYT1B
NM_004845.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07956481).

BS2

High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYT1B	NM_004845.5 link	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 8	ENST00000379144.7	NP_004836.2	Q9Y5K3-1
PCYT1B	NM_001163265.2 link	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 9		NP_001156737.1	Q9Y5K3-2
PCYT1B	XM_017029977.2 link	c.-348G>A		5_prime_UTR_variant	Exon 1 of 9		XP_016885466.1
PCYT1B	NM_001163264.2 link	c.63+25525G>A		intron_variant	Intron 1 of 7		NP_001156736.1	Q9Y5K3-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCYT1B	ENST00000379144.7 link	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 8	1	NM_004845.5	ENSP00000368439.2	Q9Y5K3-1
PCYT1B	ENST00000356768.8 link	c.61G>A	p.Glu21Lys	missense_variant	Exon 1 of 9	1		ENSP00000349211.4	Q9Y5K3-2
PCYT1B	ENST00000379145.5 link	c.63+25525G>A		intron_variant	Intron 1 of 7	1		ENSP00000368440.1	Q9Y5K3-4
PCYT1B	ENST00000496020.1 link	n.-18G>A		upstream_gene_variant		3		ENSP00000436562.1	F2Z2B1

Frequencies

GnomAD3 genomes

AF:

0.000116

AC:

AN:

111799

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33993

show subpopulations

Gnomad AFR

AF:

0.000423

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

GnomAD3 exomes

AF:

0.0000655

AC:

AN:

183318

Hom.:

AF XY:

0.0000886

AC XY:

AN XY:

67754

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000210

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1097320

Hom.:

Cov.:

AF XY:

0.00000827

AC XY:

AN XY:

362686

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000111

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.000116

AC:

AN:

111799

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33993

show subpopulations

Gnomad4 AFR

AF:

0.000423

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000200

ESP6500AA

AF:

0.00156

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.61G>A (p.E21K) 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 61, causing the glutamic acid (E) at amino acid position 21 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

0.075

BayesDel_addAF

Benign

-0.097

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

.;T

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.86

D;D

M_CAP

Benign

0.0062

MetaRNN

Benign

0.080

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

N;N

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.18

N;N

REVEL

Benign

0.15

Sift

Benign

0.33

T;D

Sift4G

Benign

0.86

T;T

Polyphen

0.34

B;B

Vest4

0.31

MVP

0.58

MPC

0.0028

ClinPred

0.033

GERP RS

4.9

Varity_R

0.31

gMVP

0.43

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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