rs543168607

Variant names:

• chr17-2595477-CAT-C
• rs543168607
• NM_000430.4:c.-191+1473_-191+1474delTA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_000430.4(PAFAH1B1):​c.-191+1473_-191+1474delTA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00364 in 147,980 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0036 (2 hom., cov: 31)
• Consequence: PAFAH1B1 NM_000430.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.19
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 17-2595477-CAT-C is Benign according to our data. Variant chr17-2595477-CAT-C is described in ClinVar as [Likely_benign]. Clinvar id is 1676350.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00364 (539/147980) while in subpopulation AFR AF = 0.0127 (509/40024). AF 95% confidence interval is 0.0118. There are 2 homozygotes in GnomAd4. There are 226 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 539 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.-191+1473_-191+1474delTA		intron_variant	Intron 1 of 10	ENST00000397195.10	NP_000421.1
PAFAH1B1	XM_011523901.3	c.-191+1473_-191+1474delTA		intron_variant	Intron 1 of 11		XP_011522203.1
PAFAH1B1	XM_011523902.4	c.-396+1085_-396+1086delTA		intron_variant	Intron 1 of 12		XP_011522204.1
PAFAH1B1	XM_017024701.2	c.-191+2149_-191+2150delTA		intron_variant	Intron 1 of 10		XP_016880190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.-191+1472_-191+1473delAT		intron_variant	Intron 1 of 10	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes AF: 0.00365 AC: 539 AN: 147870 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.0128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00327

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00294

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00364 AC: 539 AN: 147980 Hom.: 2 Cov.: 31 AF XY: 0.00315 AC XY: 226 AN XY: 71846

African (AFR) AF: 0.0127 AC: 509 AN: 40024

American (AMR) AF: 0.00150 AC: 22 AN: 14704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3454

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00 AC: 0 AN: 4678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9446

Middle Eastern (MID) AF: 0.00352 AC: 1 AN: 284

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67350

Other (OTH) AF: 0.00291 AC: 6 AN: 2060

Alfa AF: 0.00263 Hom.: 0

Bravo AF: 0.00425

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Oct 08, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2

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: rs543168607; hg19: chr17-2498771;