rs140548168

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000430.4(PAFAH1B1):​c.192+49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,315,518 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0087 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: PAFAH1B1 NM_000430.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.88
• Publications: 1 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: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 17-2666139-C-T is Benign according to our data. Variant chr17-2666139-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00869 (1323/152206) while in subpopulation AFR AF = 0.0288 (1195/41548). AF 95% confidence interval is 0.0274. There are 17 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1323 AD gene.

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.192+49C>T		intron	N/A	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.192+49C>T		intron	N/A	ENSP00000380378.4	P43034-1
	PAFAH1B1	ENST00000572915.6	TSL:1	n.273-853C>T		intron	N/A
	PAFAH1B1	ENST00000674608.1		c.246+49C>T		intron	N/A	ENSP00000501976.1	A0A6Q8PFU3

Frequencies

GnomAD3 genomes AF: 0.00865 AC: 1316 AN: 152086 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0287

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00717

GnomAD2 exomes AF: 0.00240 AC: 336 AN: 140246 AF XY: 0.00187

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.00280

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000533

Gnomad OTH exome AF: 0.00259

GnomAD4 exome AF: 0.00107 AC: 1246 AN: 1163312 Hom.: 14 Cov.: 19 AF XY: 0.00100 AC XY: 576 AN XY: 576126

African (AFR) AF: 0.0257 AC: 663 AN: 25798

American (AMR) AF: 0.00353 AC: 93 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: 0.000131 AC: 9 AN: 68908

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

Middle Eastern (MID) AF: 0.00839 AC: 29 AN: 3456

European-Non Finnish (NFE) AF: 0.000321 AC: 286 AN: 892134

Other (OTH) AF: 0.00343 AC: 166 AN: 48402

GnomAD4 genome AF: 0.00869 AC: 1323 AN: 152206 Hom.: 17 Cov.: 32 AF XY: 0.00825 AC XY: 614 AN XY: 74402

African (AFR) AF: 0.0288 AC: 1195 AN: 41548

American (AMR) AF: 0.00582 AC: 89 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10562

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68002

Other (OTH) AF: 0.00710 AC: 15 AN: 2114

Alfa AF: 0.00493 Hom.: 2

Bravo AF: 0.0104

Asia WGS AF: 0.00231 AC: 8 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.49
DANN	Benign	0.70
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

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;