17-78403724-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024419.5(PGS1):c.1037C>A(p.Ala346Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PGS1 NM_024419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.69

Genes affected

PGS1 (HGNC:30029): (phosphatidylglycerophosphate synthase 1) Predicted to enable CDP-diacylglycerol-glycerol-3-phosphate 3-phosphatidyltransferase activity and calcium ion binding activity. Predicted to be involved in cardiolipin biosynthetic process and diacylglycerol metabolic process. Located in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061540574).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGS1	NM_024419.5	c.1037C>A	p.Ala346Asp	missense_variant	7/10	ENST00000262764.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGS1	ENST00000262764.11	c.1037C>A	p.Ala346Asp	missense_variant	7/10	1	NM_024419.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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

Dec 08, 2023

The c.1037C>A (p.A346D) alteration is located in exon 7 (coding exon 7) of the PGS1 gene. This alteration results from a C to A substitution at nucleotide position 1037, causing the alanine (A) at amino acid position 346 to be replaced by an aspartic acid (D). 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	0.11
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	16
Dann	Benign	0.91
DEOGEN2	Benign	0.017	T;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.062	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.53	N;.
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.12	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.63	T;.
Sift4G	Benign	0.65	T;T
Polyphen		0.16	B;.
Vest4		0.25
MutPred		0.30		Gain of disorder (P = 0.0727);.;
MVP		0.53
MPC		0.66
ClinPred		0.060	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.046
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1598329160; hg19: chr17-76399805;