Genetic Variant NM_000430.4:c.84T>C (chr17-2665423-T-C) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_000430.4(PAFAH1B1):c.84T>C(p.Tyr28Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PAFAH1B1
NM_000430.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.19

Publications

2 publications found

Variant links:

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)

PAFAH1B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP7

Synonymous conserved (PhyloP=1.19 with no splicing effect.

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.84T>C	p.Tyr28Tyr	synonymous	Exon 3 of 11	NP_000421.1	P43034-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PAFAH1B1	ENST00000397195.10	TSL:1 MANE Select	c.84T>C	p.Tyr28Tyr	synonymous	Exon 3 of 11	ENSP00000380378.4	P43034-1
PAFAH1B1	ENST00000572915.6	TSL:1	n.273-1569T>C		intron	N/A
PAFAH1B1	ENST00000674608.1		c.138T>C	p.Tyr46Tyr	synonymous	Exon 4 of 12	ENSP00000501976.1	A0A6Q8PFU3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251004

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1455196

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

724242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33336

American (AMR)

AF:

0.00

AC:

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26084

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

86050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5018

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1107076

Other (OTH)

AF:

0.00

AC:

AN:

60110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

8.6

(source)

DANN

Benign

0.41

PhyloP100

1.2

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over