PAFAH1B1 p.Lys64Asn

Variant names:

• chr17-2666090-G-T
• NM_000430.4:c.192G>T
• PAFAH1B1 p.Lys64Asn

Your query was ambiguous. Multiple possible variants found:

• chr17-2666090-G-T
• chr17-2666090-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000430.4(PAFAH1B1):​c.192G>T​(p.Lys64Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K64E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PAFAH1B1 NM_000430.4 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.59
• Publications: 0 publications found

Genes affected

PAFAH1B1 (HGNC:8574): (platelet activating factor acetylhydrolase 1b regulatory subunit 1) This locus was identified as encoding a gene that when mutated or lost caused the lissencephaly associated with Miller-Dieker lissencephaly syndrome. This gene encodes the non-catalytic alpha subunit of the intracellular Ib isoform of platelet-activating factor acteylhydrolase, a heterotrimeric enzyme that specifically 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). Two other isoforms of intracellular platelet-activating factor acetylhydrolase exist: one composed of multiple subunits, the other, a single subunit. In addition, a single-subunit isoform of this enzyme is found in serum. [provided by RefSeq, Apr 2009]

PAFAH1B1 Gene-Disease associations (from GenCC):

• lissencephaly due to LIS1 mutation

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000430.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	NM_000430.4	MANE Select	c.192G>T	p.Lys64Asn	missense splice_region	Exon 4 of 11	NP_000421.1	P43034-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	ENST00000397195.10	TSL:1 MANE Select	c.192G>T	p.Lys64Asn	missense splice_region	Exon 4 of 11	ENSP00000380378.4	P43034-1
	PAFAH1B1	ENST00000572915.6	TSL:1	n.273-902G>T		intron	N/A
	PAFAH1B1	ENST00000570400.2	TSL:3	c.-4G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 11	ENSP00000460258.2	A0A6Q8PFT2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.084	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	3.4	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Varity_R		0.86
gMVP		0.91
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.96		Position offset: 0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr17-2569384;