Genetic Variant PCYT1B:p.His161Tyr (chrX-24590028-G-A) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_004845.5(PCYT1B):c.481C>T(p.His161Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000325 in 1,201,289 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000034 ( 0 hom. 12 hem. )

Consequence

PCYT1B
NM_004845.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.60

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.834

BS2

High Hemizygotes in GnomAdExome4 at 12 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYT1B	NM_004845.5 link	c.481C>T	p.His161Tyr	missense_variant	Exon 4 of 8	ENST00000379144.7	NP_004836.2	Q9Y5K3-1
PCYT1B	NM_001163264.2 link	c.427C>T	p.His143Tyr	missense_variant	Exon 4 of 8		NP_001156736.1	Q9Y5K3-4
PCYT1B	NM_001163265.2 link	c.481C>T	p.His161Tyr	missense_variant	Exon 4 of 9		NP_001156737.1	Q9Y5K3-2
PCYT1B	XM_017029977.2 link	c.193C>T	p.His65Tyr	missense_variant	Exon 5 of 9		XP_016885466.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PCYT1B	ENST00000379144.7 link	c.481C>T	p.His161Tyr	missense_variant	Exon 4 of 8	1	NM_004845.5	ENSP00000368439.2	Q9Y5K3-1
PCYT1B	ENST00000379145.5 link	c.427C>T	p.His143Tyr	missense_variant	Exon 4 of 8	1		ENSP00000368440.1	Q9Y5K3-4
PCYT1B	ENST00000356768.8 link	c.481C>T	p.His161Tyr	missense_variant	Exon 4 of 9	1		ENSP00000349211.4	Q9Y5K3-2
PCYT1B	ENST00000496020.1 link	n.403C>T		non_coding_transcript_exon_variant	Exon 4 of 7	3		ENSP00000436562.1	F2Z2B1

Frequencies

GnomAD3 genomes

AF:

0.0000179

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33921

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000376

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000115

AC:

AN:

174394

Hom.:

AF XY:

0.0000168

AC XY:

AN XY:

59686

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000253

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000340

AC:

AN:

1089546

Hom.:

Cov.:

AF XY:

0.0000337

AC XY:

AN XY:

355748

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000247

Gnomad4 NFE exome

AF:

0.0000430

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000179

AC:

AN:

111743

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33921

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000376

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000346

AC:

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

Nov 23, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.481C>T (p.H161Y) alteration is located in exon 4 (coding exon 4) of the PCYT1B gene. This alteration results from a C to T substitution at nucleotide position 481, causing the histidine (H) at amino acid position 161 to be replaced by a tyrosine (Y). 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

0.27

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.49

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.70

MetaRNN

Pathogenic

0.83

D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

1.3

.;L;L

PrimateAI

Pathogenic

0.94

PROVEAN

Pathogenic

-5.3

D;D;D

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0060

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Polyphen

0.98, 0.92

.;D;P

Vest4

0.78

MutPred

0.53

.;Gain of sheet (P = 0.0028);Gain of sheet (P = 0.0028);

MVP

0.98

MPC

2.1

ClinPred

0.88

GERP RS

5.4

Varity_R

0.86

gMVP

0.98

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