rs587777190

Positions:

• chr3-196247405-G-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001312673.2(PCYT1A):​c.448C>G​(p.Pro150Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PCYT1A NM_001312673.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.60

Genes affected

PCYT1A (HGNC:8754): (phosphate cytidylyltransferase 1A, choline) This gene belongs to the cytidylyltransferase family and is involved in the regulation of phosphatidylcholine biosynthesis. Mutations in this gene are associated with spondylometaphyseal dysplasia with cone-rod dystrophy. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant 3-196247405-G-C is Pathogenic according to our data. Variant chr3-196247405-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 101058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-196247405-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PCYT1A	NM_001312673.2	c.448C>G	p.Pro150Ala	missense_variant	5/9	ENST00000431016.6	NP_001299602.1
PCYT1A	NM_005017.4	c.448C>G	p.Pro150Ala	missense_variant	6/10		NP_005008.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PCYT1A	ENST00000431016.6	c.448C>G	p.Pro150Ala	missense_variant	5/9	1	NM_001312673.2	ENSP00000394617.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251436 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135890

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: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727238

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: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondylometaphyseal dysplasia-cone-rod dystrophy syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	research	Baylor-Hopkins Center for Mendelian Genomics, Johns Hopkins University School of Medicine	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 02, 2014	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects PCYT1A function (PMID: 30559292). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PCYT1A protein function. ClinVar contains an entry for this variant (Variation ID: 101058). This missense change has been observed in individual(s) with spondylometaphyseal dysplasia (PMID: 24387990). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs587777190, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 150 of the PCYT1A protein (p.Pro150Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;D;D;D;D;.;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;.;D;D;D;D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;.;H;H;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-8.0	D;D;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	.;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;.
Vest4		0.96, 0.93, 0.93
MutPred		0.62		Gain of catalytic residue at P150 (P = 0.0107);Gain of catalytic residue at P150 (P = 0.0107);Gain of catalytic residue at P150 (P = 0.0107);Gain of catalytic residue at P150 (P = 0.0107);Gain of catalytic residue at P150 (P = 0.0107);.;.;
MVP		0.97
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.97
gMVP		0.97

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: rs587777190; hg19: chr3-195974276;