rs140548168

Variant names:

• chr17-2666139-C-A
• rs140548168
• NM_000430.4:c.192+49C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-2666139-C-A
• chr17-2666139-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000430.4(PAFAH1B1):​c.192+49C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000086 in 1,163,334 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
• Consequence: PAFAH1B1 NM_000430.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.88
• 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	NM_000430.4	MANE Select	c.192+49C>A		intron	N/A	NP_000421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PAFAH1B1	ENST00000397195.10	TSL:1 MANE Select	c.192+49C>A		intron	N/A	ENSP00000380378.4
	PAFAH1B1	ENST00000572915.6	TSL:1	n.273-853C>A		intron	N/A
	PAFAH1B1	ENST00000674608.1		c.246+49C>A		intron	N/A	ENSP00000501976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.60e-7 AC: 1 AN: 1163334 Hom.: 0 Cov.: 19 AF XY: 0.00 AC XY: 0 AN XY: 576136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 25808

American (AMR) AF: 0.00 AC: 0 AN: 26322

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21772

East Asian (EAS) AF: 0.00 AC: 0 AN: 33190

South Asian (SAS) AF: 0.00 AC: 0 AN: 68908

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3458

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 892136

Other (OTH) AF: 0.00 AC: 0 AN: 48410

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.39
DANN	Benign	0.71
PhyloP100		-1.9

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

Other links and lift over

dbSNP: rs140548168; hg19: chr17-2569433;