rs6628

Variant names:

• chr17-2681819-C-T
• rs6628
• NM_000430.4:c.*17C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000430.4(PAFAH1B1):​c.*17C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,589,384 control chromosomes in the GnomAD database, including 45,961 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3240 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42721 hom.)
• Consequence: PAFAH1B1 NM_000430.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.27
• Publications: 13 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 17-2681819-C-T is Benign according to our data. Variant chr17-2681819-C-T is described in ClinVar as Benign. ClinVar VariationId is 42175.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

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.*17C>T		3_prime_UTR	Exon 11 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.*17C>T		3_prime_UTR	Exon 11 of 11	ENSP00000380378.4	P43034-1
	PAFAH1B1	ENST00000572915.6	TSL:1	n.677-1769C>T		intron	N/A
	PAFAH1B1	ENST00000674608.1		c.*17C>T		3_prime_UTR	Exon 12 of 12	ENSP00000501976.1	A0A6Q8PFU3

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30122 AN: 151862 Hom.: 3244 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.178

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.0480

Gnomad SAS AF: 0.136

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.185

GnomAD2 exomes AF: 0.200 AC: 49213 AN: 246630 AF XY: 0.202

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.0491

Gnomad FIN exome AF: 0.195

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.211

GnomAD4 exome AF: 0.237 AC: 341329 AN: 1437404 Hom.: 42721 Cov.: 26 AF XY: 0.235 AC XY: 168435 AN XY: 715806

African (AFR) AF: 0.125 AC: 4143 AN: 33100

American (AMR) AF: 0.175 AC: 7753 AN: 44296

Ashkenazi Jewish (ASJ) AF: 0.248 AC: 6431 AN: 25896

East Asian (EAS) AF: 0.0396 AC: 1570 AN: 39602

South Asian (SAS) AF: 0.154 AC: 13166 AN: 85374

European-Finnish (FIN) AF: 0.195 AC: 10405 AN: 53272

Middle Eastern (MID) AF: 0.199 AC: 822 AN: 4140

European-Non Finnish (NFE) AF: 0.260 AC: 283770 AN: 1092220

Other (OTH) AF: 0.223 AC: 13269 AN: 59504

GnomAD4 genome AF: 0.198 AC: 30123 AN: 151980 Hom.: 3240 Cov.: 32 AF XY: 0.193 AC XY: 14326 AN XY: 74284

African (AFR) AF: 0.130 AC: 5387 AN: 41460

American (AMR) AF: 0.178 AC: 2710 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 848 AN: 3470

East Asian (EAS) AF: 0.0477 AC: 247 AN: 5176

South Asian (SAS) AF: 0.136 AC: 656 AN: 4810

European-Finnish (FIN) AF: 0.199 AC: 2093 AN: 10536

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17422 AN: 67958

Other (OTH) AF: 0.182 AC: 385 AN: 2112

Alfa AF: 0.226 Hom.: 743

Bravo AF: 0.194

Asia WGS AF: 0.0950 AC: 332 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	-	Lissencephaly due to LIS1 mutation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	14
DANN	Benign	0.80
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism (auto)

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: rs6628; hg19: chr17-2585113;