Genetic Variant PCYT1B:p.Gln54His (chrX-24619040-C-G) – 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.162G>C(p.Gln54His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000126 in 1,190,031 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000093 ( 0 hom. 5 hem. )

Consequence

PCYT1B
NM_004845.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.459

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=0.11972046).

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYT1B	NM_004845.5 link	c.162G>C	p.Gln54His	missense_variant	Exon 2 of 8	ENST00000379144.7	NP_004836.2	Q9Y5K3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCYT1B	ENST00000379144.7 link	c.162G>C	p.Gln54His	missense_variant	Exon 2 of 8	1	NM_004845.5	ENSP00000368439.2	Q9Y5K3-1
PCYT1B	ENST00000379145.5 link	c.108G>C	p.Gln36His	missense_variant	Exon 2 of 8	1		ENSP00000368440.1	Q9Y5K3-4
PCYT1B	ENST00000356768.8 link	c.162G>C	p.Gln54His	missense_variant	Exon 2 of 9	1		ENSP00000349211.4	Q9Y5K3-2
PCYT1B	ENST00000496020.1 link	n.84G>C		non_coding_transcript_exon_variant	Exon 2 of 7	3		ENSP00000436562.1	F2Z2B1

Frequencies

GnomAD3 genomes

AF:

0.0000448

AC:

AN:

111693

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33871

show subpopulations

Gnomad AFR

AF:

0.0000325

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000383

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:

0.0000238

AC:

AN:

167796

Hom.:

AF XY:

0.0000185

AC XY:

AN XY:

54132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000157

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:

0.00000927

AC:

AN:

1078338

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

347404

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000235

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:

0.0000442

GnomAD4 genome

AF:

0.0000448

AC:

AN:

111693

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33871

show subpopulations

Gnomad4 AFR

AF:

0.0000325

Gnomad4 AMR

AF:

0.000383

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:

0.000223

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.162G>C (p.Q54H) alteration is located in exon 2 (coding exon 2) of the PCYT1B gene. This alteration results from a G to C substitution at nucleotide position 162, causing the glutamine (Q) at amino acid position 54 to be replaced by a histidine (H). 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

0.086

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.17

.;.;T

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.2

N;N;N

REVEL

Benign

0.067

Sift

Benign

0.11

T;T;T

Sift4G

Benign

0.12

T;T;T

Polyphen

0.41, 0.58

.;B;P

Vest4

0.21

MutPred

0.39

.;Loss of helix (P = 0.0033);Loss of helix (P = 0.0033);

MVP

0.34

MPC

0.0030

ClinPred

0.079

GERP RS

-0.15

Varity_R

0.089

gMVP

0.47

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