chr19-42302255-C-T

Variant names:

• chr19-42302255-C-T
• rs145667000
• NM_002573.4:c.55G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002573.4(PAFAH1B3):​c.55G>A​(p.Gly19Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000107 in 1,605,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: PAFAH1B3 NM_002573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

Genes affected

PAFAH1B3 (HGNC:8576): (platelet activating factor acetylhydrolase 1b catalytic subunit 3) This gene encodes an acetylhydrolase that catalyzes the removal of an acetyl group from the glycerol backbone of platelet-activating factor. The encoded enzyme is a subunit of the platelet-activating factor acetylhydrolase isoform 1B complex, which consists of the catalytic beta and gamma subunits and the regulatory alpha subunit. This complex functions in brain development. A translocation between this gene on chromosome 19 and the CDC-like kinase 2 gene on chromosome 1 has been observed, and was associated with cognitive disability, ataxia, and atrophy of the brain. Alternatively spliced transcript variants have been described. [provided by RefSeq, Mar 2009]

PRR19 (HGNC:33728): (proline rich 19)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26275516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B3	NM_002573.4	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 5	ENST00000262890.8	NP_002564.1
PRR19	NM_199285.3	c.-255C>T		5_prime_UTR_variant	Exon 1 of 3	ENST00000341747.8	NP_954979.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B3	ENST00000262890.8	c.55G>A	p.Gly19Ser	missense_variant	Exon 1 of 5	1	NM_002573.4	ENSP00000262890.2
PRR19	ENST00000341747	c.-255C>T		5_prime_UTR_variant	Exon 1 of 3	5	NM_199285.3	ENSP00000342709.3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000150 AC: 35 AN: 233294 Hom.: 0 AF XY: 0.000174 AC XY: 22 AN XY: 126458

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000331

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: 0.000190

Gnomad OTH exome AF: 0.000692

GnomAD4 exome AF: 0.000105 AC: 153 AN: 1452760 Hom.: 0 Cov.: 31 AF XY: 0.000112 AC XY: 81 AN XY: 721778

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000183

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: 0.000108

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74500

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000150 Hom.: 0

Bravo AF: 0.000196

ExAC AF: 0.0000991 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55G>A (p.G19S) alteration is located in exon 2 (coding exon 1) of the PAFAH1B3 gene. This alteration results from a G to A substitution at nucleotide position 55, causing the glycine (G) at amino acid position 19 to be replaced by a serine (S). 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	0.71
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D;D;.;.;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Pathogenic	2.9	M;M;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.7	D;D;.;.;.;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0040	D;D;.;.;.;.
Sift4G	Benign	0.066	T;T;.;.;.;T
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.32
MVP		0.68
MPC		1.2
ClinPred		0.84	D
GERP RS		3.4
Varity_R		0.67
gMVP		0.53

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: rs145667000; hg19: chr19-42806407;