NM_000430.4:c.-191+1431_-191+1432insTTCTT

Variant names:

• chr17-2595435-T-TTTTTC
• rs1188566045
• NM_000430.4:c.-191+1431_-191+1432insTTCTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_000430.4(PAFAH1B1):​c.-191+1431_-191+1432insTTCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 150,950 control chromosomes in the GnomAD database, including 172 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.022 (172 hom., cov: 30)
• Consequence: PAFAH1B1 NM_000430.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.516
• 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 17-2595435-T-TTTTTC is Benign according to our data. Variant chr17-2595435-T-TTTTTC is described in ClinVar as [Benign]. Clinvar id is 1301273.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PAFAH1B1	NM_000430.4	c.-191+1431_-191+1432insTTCTT		intron_variant	Intron 1 of 10	ENST00000397195.10	NP_000421.1
PAFAH1B1	XM_011523901.3	c.-191+1431_-191+1432insTTCTT		intron_variant	Intron 1 of 11		XP_011522203.1
PAFAH1B1	XM_011523902.4	c.-396+1043_-396+1044insTTCTT		intron_variant	Intron 1 of 12		XP_011522204.1
PAFAH1B1	XM_017024701.2	c.-191+2107_-191+2108insTTCTT		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+1429_-191+1430insTTTTC		intron_variant	Intron 1 of 10	1	NM_000430.4	ENSP00000380378.4

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3263 AN: 150858 Hom.: 172 Cov.: 30

Gnomad AFR AF: 0.0767

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00646

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0183

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

GnomAD4 genome AF: 0.0217 AC: 3270 AN: 150950 Hom.: 172 Cov.: 30 AF XY: 0.0217 AC XY: 1602 AN XY: 73776

African (AFR) AF: 0.0767 AC: 3116 AN: 40640

American (AMR) AF: 0.00645 AC: 98 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10480

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000221 AC: 15 AN: 67878

Other (OTH) AF: 0.0181 AC: 38 AN: 2104

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 28, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1188566045; hg19: chr17-2498729;