rs140936904

Positions:

• chr17-2667186-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_000430.4(PAFAH1B1):​c.387T>C​(p.Asp129=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000583 in 1,612,922 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00055 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (4 hom.)
• Consequence: PAFAH1B1 NM_000430.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 1.39

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-2667186-T-C is Benign according to our data. Variant chr17-2667186-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 159518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=2, Uncertain_significance=1}. Variant chr17-2667186-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000552 (84/152222) while in subpopulation AMR AF= 0.00131 (20/15286). AF 95% confidence interval is 0.000866. There are 0 homozygotes in gnomad4. There are 46 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 84 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.387T>C	p.Asp129=	synonymous_variant	5/11	ENST00000397195.10	NP_000421.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PAFAH1B1	ENST00000397195.10	c.387T>C	p.Asp129=	synonymous_variant	5/11	1	NM_000430.4	ENSP00000380378	P1

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152104 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.000961

GnomAD3 exomes AF: 0.000972 AC: 244 AN: 251134 Hom.: 0 AF XY: 0.000936 AC XY: 127 AN XY: 135728

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00585

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000523

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000670

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000586 AC: 856 AN: 1460700 Hom.: 4 Cov.: 30 AF XY: 0.000629 AC XY: 457 AN XY: 726750

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00589

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000349

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74428

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.000951

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000767

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PAFAH1B1: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2019	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	12
DANN	Benign	0.64

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: rs140936904; hg19: chr17-2570480;