chr1-25984487-C-T

Variant names:

• chr1-25984487-C-T
• rs749673118
• NM_000437.4:c.383G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000437.4(PAFAH2):​c.383G>A​(p.Gly128Asp) variant causes a missense change. The variant allele was found at a frequency of 0.0000205 in 1,461,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PAFAH2 NM_000437.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.59

Genes affected

PAFAH2 (HGNC:8579): (platelet activating factor acetylhydrolase 2) This gene encodes platelet-activating factor acetylhydrolase isoform 2, a single-subunit intracellular enzyme that catalyzes the removal of the acetyl group at the SN-2 position of platelet-activating factor (identified as 1-O-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine). However, this lipase exhibits a broader substrate specificity than simply platelet activating factor. Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist, and both are multi-subunit enzymes. Additionally, there is a single-subunit serum isoform of this enzyme. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH2	NM_000437.4	c.383G>A	p.Gly128Asp	missense_variant	Exon 5 of 11	ENST00000374282.8	NP_000428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH2	ENST00000374282.8	c.383G>A	p.Gly128Asp	missense_variant	Exon 5 of 11	1	NM_000437.4	ENSP00000363400.3
PAFAH2	ENST00000439092.6	c.383G>A	p.Gly128Asp	missense_variant	Exon 5 of 6	3		ENSP00000408313.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000399 AC: 10 AN: 250584 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135490

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: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461640 Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22 AN XY: 727118

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: 0.000336

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.383G>A (p.G128D) alteration is located in exon 5 (coding exon 4) of the PAFAH2 gene. This alteration results from a G to A substitution at nucleotide position 383, causing the glycine (G) at amino acid position 128 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	Pathogenic	0.59
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;T;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;D;D;D
M_CAP	Benign	0.077	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Uncertain	0.011	D
MutationAssessor	Pathogenic	3.4	M;M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.8	D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;.
Polyphen		1.0	D;D;.;.
Vest4		0.94
MutPred		0.98		Gain of catalytic residue at G128 (P = 0.1265);Gain of catalytic residue at G128 (P = 0.1265);Gain of catalytic residue at G128 (P = 0.1265);Gain of catalytic residue at G128 (P = 0.1265);
MVP		0.82
MPC		0.45
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs749673118; hg19: chr1-26310978;