19-42297305-C-T

Variant names:

• chr19-42297305-C-T
• rs143760547
• NM_002573.4:c.469G>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.469G>A​(p.Glu157Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: PAFAH1B3 NM_002573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.274

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]

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=0.1402232).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B3	NM_002573.4	c.469G>A	p.Glu157Lys	missense_variant	Exon 5 of 5	ENST00000262890.8	NP_002564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B3	ENST00000262890.8	c.469G>A	p.Glu157Lys	missense_variant	Exon 5 of 5	1	NM_002573.4	ENSP00000262890.2

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000359 AC: 9 AN: 250918 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461496 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 726976

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000558

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74476

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.469G>A (p.E157K) alteration is located in exon 6 (coding exon 5) of the PAFAH1B3 gene. This alteration results from a G to A substitution at nucleotide position 469, causing the glutamic acid (E) at amino acid position 157 to be replaced by a lysine (K). 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	0.13
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T;.
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.80	.;T;T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.46	N;N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.89	N;N;.
REVEL	Benign	0.041
Sift	Benign	0.39	T;T;.
Sift4G	Benign	0.60	T;T;.
Polyphen		0.19	B;B;.
Vest4		0.17
MVP		0.56
MPC		0.46
ClinPred		0.043	T
GERP RS		3.8
Varity_R		0.045
gMVP		0.45

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: rs143760547; hg19: chr19-42801457;