chrX-24562316-C-T

Variant names:

• chrX-24562316-C-T
• rs781320489
• NM_004845.5:c.1087G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_004845.5(PCYT1B):​c.1087G>A​(p.Glu363Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000668 in 1,047,957 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000067 (0 hom. 3 hem.)
• Consequence: PCYT1B NM_004845.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BS2: High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCYT1B	NM_004845.5	c.1087G>A	p.Glu363Lys	missense_variant	Exon 8 of 8	ENST00000379144.7	NP_004836.2
PCYT1B	NM_001163264.2	c.1033G>A	p.Glu345Lys	missense_variant	Exon 8 of 8		NP_001156736.1
PCYT1B	XM_017029977.2	c.799G>A	p.Glu267Lys	missense_variant	Exon 9 of 9		XP_016885466.1
PCYT1B	NM_001163265.2	c.960+127G>A		intron_variant	Intron 8 of 8		NP_001156737.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCYT1B	ENST00000379144.7	c.1087G>A	p.Glu363Lys	missense_variant	Exon 8 of 8	1	NM_004845.5	ENSP00000368439.2
PCYT1B	ENST00000379145.5	c.1033G>A	p.Glu345Lys	missense_variant	Exon 8 of 8	1		ENSP00000368440.1
PCYT1B	ENST00000356768.8	c.960+127G>A		intron_variant	Intron 8 of 8	1		ENSP00000349211.4
PCYT1B	ENST00000496020.1	n.*396G>A		downstream_gene_variant		3		ENSP00000436562.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000668 AC: 7 AN: 1047957 Hom.: 0 Cov.: 30 AF XY: 0.00000898 AC XY: 3 AN XY: 333939

Gnomad4 AFR exome AF: 0.0000399

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: 0.00

Gnomad4 NFE exome AF: 0.00000734

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 17, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1087G>A (p.E363K) alteration is located in exon 8 (coding exon 8) of the PCYT1B gene. This alteration results from a G to A substitution at nucleotide position 1087, causing the glutamic acid (E) at amino acid position 363 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	Uncertain	0.42
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	.;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.041	D
MetaRNN	Uncertain	0.48	T;T
MetaSVM	Benign	-0.40	T
MutationAssessor	Benign	0.42	.;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.83	N;N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.078	T;T
Polyphen		0.99	.;D
Vest4		0.63
MutPred		0.14		.;Gain of ubiquitination at E363 (P = 0.0039);
MVP		0.75
MPC		2.2
ClinPred		0.98	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.60

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

Other links and lift over

dbSNP: rs781320489; hg19: chrX-24580433; COSMIC: COSV100770968; COSMIC: COSV100770968;