X-24590024-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004845.5(PCYT1B):c.485A>G(p.Lys162Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000092 in 1,087,370 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: PCYT1B NM_004845.5 missense, splice_region
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.95

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PCYT1B	NM_004845.5	c.485A>G	p.Lys162Arg	missense_variant, splice_region_variant	4/8	ENST00000379144.7
PCYT1B	NM_001163264.2	c.431A>G	p.Lys144Arg	missense_variant, splice_region_variant	4/8
PCYT1B	NM_001163265.2	c.485A>G	p.Lys162Arg	missense_variant, splice_region_variant	4/9
PCYT1B	XM_017029977.2	c.197A>G	p.Lys66Arg	missense_variant, splice_region_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PCYT1B	ENST00000379144.7	c.485A>G	p.Lys162Arg	missense_variant, splice_region_variant	4/8	1	NM_004845.5	P1
PCYT1B	ENST00000379145.5	c.431A>G	p.Lys144Arg	missense_variant, splice_region_variant	4/8	1
PCYT1B	ENST00000356768.8	c.485A>G	p.Lys162Arg	missense_variant, splice_region_variant	4/9	1
PCYT1B	ENST00000496020.1	c.407A>G	p.Lys136Arg	missense_variant, splice_region_variant, NMD_transcript_variant	4/7	3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000575 AC: 1 AN: 173781 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 59105

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: 0.0000602

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087370 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 353734

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: 0.0000191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.485A>G (p.K162R) alteration is located in exon 4 (coding exon 4) of the PCYT1B gene. This alteration results from a A to G substitution at nucleotide position 485, causing the lysine (K) at amino acid position 162 to be replaced by an arginine (R). 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	0.083
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.16
Cadd	Benign	23
Dann	Uncertain	0.99
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Uncertain	0.46	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.59
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.36	T;T;T
Polyphen		0.016, 0.010	.;B;B
Vest4		0.24
MutPred		0.48		.;Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.98
MPC		1.2
ClinPred		0.35	T
GERP RS		5.4
Varity_R		0.48
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.17		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: rs770144930; hg19: chrX-24608141;