17-78403873-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_024419.5(PGS1):c.1186A>G(p.Met396Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PGS1 NM_024419.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.96

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PGS1	NM_024419.5	c.1186A>G	p.Met396Val	missense_variant	7/10	ENST00000262764.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PGS1	ENST00000262764.11	c.1186A>G	p.Met396Val	missense_variant	7/10	1	NM_024419.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461836 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

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 21, 2022

The c.1186A>G (p.M396V) alteration is located in exon 7 (coding exon 7) of the PGS1 gene. This alteration results from a A to G substitution at nucleotide position 1186, causing the methionine (M) at amino acid position 396 to be replaced by a valine (V). 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	0.10
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.081	T;T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.57	D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N;.
REVEL	Pathogenic	0.73
Sift	Benign	0.26	T;.
Sift4G	Benign	0.11	T;T
Polyphen		0.90	P;.
Vest4		0.42
MutPred		0.53		Loss of phosphorylation at Y395 (P = 0.1457);.;
MVP		0.81
MPC		0.45
ClinPred		0.44	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-76399954;