chr19-42302280-C-G

Variant names:

• chr19-42302280-C-G
• rs747110583
• NM_002573.4:c.30G>C

Variant summary

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

The NM_002573.4(PAFAH1B3):​c.30G>C​(p.Lys10Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,858 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PAFAH1B3 NM_002573.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.722

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=0.07233459).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B3	NM_002573.4	c.30G>C	p.Lys10Asn	missense_variant	Exon 1 of 5	ENST00000262890.8	NP_002564.1
PRR19	NM_199285.3	c.-230C>G		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.30G>C	p.Lys10Asn	missense_variant	Exon 1 of 5	1	NM_002573.4	ENSP00000262890.2
PRR19	ENST00000341747	c.-230C>G		5_prime_UTR_variant	Exon 1 of 3	5	NM_199285.3	ENSP00000342709.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000845 AC: 2 AN: 236640 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 128346

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000344 AC: 5 AN: 1454858 Hom.: 0 Cov.: 31 AF XY: 0.00000415 AC XY: 3 AN XY: 723074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000127

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000825 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.30G>C (p.K10N) alteration is located in exon 2 (coding exon 1) of the PAFAH1B3 gene. This alteration results from a G to C substitution at nucleotide position 30, causing the lysine (K) at amino acid position 10 to be replaced by an asparagine (N). 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	0.33
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T;.;.;.;T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.81	.;T;T;T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.072	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.34	N;N;.;.;.;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.71	N;N;.;.;.;.
REVEL	Benign	0.063
Sift	Benign	0.067	T;T;.;.;.;.
Sift4G	Benign	0.48	T;T;.;.;.;T
Polyphen		0.0030	B;B;.;.;.;.
Vest4		0.032
MutPred		0.24		Loss of ubiquitination at K10 (P = 0.0014);Loss of ubiquitination at K10 (P = 0.0014);Loss of ubiquitination at K10 (P = 0.0014);Loss of ubiquitination at K10 (P = 0.0014);Loss of ubiquitination at K10 (P = 0.0014);Loss of ubiquitination at K10 (P = 0.0014);
MVP		0.53
MPC		0.46
ClinPred		0.20	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.29

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: rs747110583; hg19: chr19-42806432;