19-10111519-A-G

Variant names:

• chr19-10111519-A-G
• rs12460842
• NM_020230.7:c.*354A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020230.7(PPAN):​c.*354A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.583 in 661,124 control chromosomes in the GnomAD database, including 113,936 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars).

• Frequency:
  • Genomes: 𝑓 0.56 (24108 hom., cov: 32)
  • Exomes 𝑓: 0.59 (89828 hom.)
• Consequence: PPAN NM_020230.7 3_prime_UTR
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: -0.269
• Publications: 24 publications found

Genes affected

PPAN (HGNC:9227): (peter pan homolog) The protein encoded by this gene is an evolutionarily conserved protein similar to yeast SSF1 as well as to the gene product of the Drosophila gene peter pan (ppan). SSF1 is known to be involved in the second step of mRNA splicing. Both SSF1 and ppan are essential for cell growth and proliferation. Exogenous expression of this gene was reported to reduce the anchorage-independent growth of some tumor cells. Read-through transcription of this gene with P2RY11/P2Y(11), an adjacent downstream gene that encodes an ATP receptor, has been found. These read-through transcripts are ubiquitously present and up-regulated during granulocyte differentiation. [provided by RefSeq, Nov 2010]

PPAN-P2RY11 (HGNC:33526): (PPAN-P2RY11 readthrough) This locus represents naturally occurring read-through transcription between the adjacent PPAN and P2RY11 genes. Alternative splicing results in two transcript variants, one of which encodes a fusion protein that shares sequence identity with each individual gene product. This transcript is found to be ubiquitously expressed and is up-regulated by agents inducing granulocytic differentiation. However, its functional significance in vivo remains unclear. [provided by RefSeq, Nov 2010]

P2RY11 (HGNC:8540): (purinergic receptor P2Y11) The product of this gene belongs to the family of G-protein coupled receptors. This family has several receptor subtypes with different pharmacological selectivity, which overlaps in some cases, for various adenosine and uridine nucleotides. This receptor is coupled to the stimulation of the phosphoinositide and adenylyl cyclase pathways and behaves as a selective purinoceptor. Naturally occuring read-through transcripts, resulting from intergenic splicing between this gene and an immediately upstream gene (PPAN, encoding peter pan homolog), have been found. The PPAN-P2RY11 read-through mRNA is ubiquitously expressed and encodes a fusion protein that shares identity with each individual gene product. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.706 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020230.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPAN	NM_020230.7	MANE Select	c.*354A>G		3_prime_UTR	Exon 12 of 12	NP_064615.3
	PPAN	NM_001346139.1		c.*354A>G		3_prime_UTR	Exon 12 of 12	NP_001333068.1
	PPAN	NM_001346141.1		c.*354A>G		3_prime_UTR	Exon 11 of 11	NP_001333070.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPAN	ENST00000253107.12	TSL:1 MANE Select	c.*354A>G		3_prime_UTR	Exon 12 of 12	ENSP00000253107.7
	PPAN-P2RY11	ENST00000393796.4	TSL:1	c.1279+497A>G		intron	N/A	ENSP00000377385.4
	PPAN	ENST00000486482.1	TSL:2	n.902A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.557 AC: 84557 AN: 151814 Hom.: 24089 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.638

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.725

Gnomad SAS AF: 0.694

Gnomad FIN AF: 0.604

Gnomad MID AF: 0.494

Gnomad NFE AF: 0.562

Gnomad OTH AF: 0.594

GnomAD4 exome AF: 0.590 AC: 300603 AN: 509190 Hom.: 89828 Cov.: 6 AF XY: 0.596 AC XY: 159530 AN XY: 267886

African (AFR) AF: 0.471 AC: 6652 AN: 14130

American (AMR) AF: 0.679 AC: 16159 AN: 23782

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 8188 AN: 14914

East Asian (EAS) AF: 0.717 AC: 22565 AN: 31488

South Asian (SAS) AF: 0.680 AC: 33988 AN: 49968

European-Finnish (FIN) AF: 0.593 AC: 18243 AN: 30746

Middle Eastern (MID) AF: 0.526 AC: 1126 AN: 2140

European-Non Finnish (NFE) AF: 0.565 AC: 177389 AN: 313826

Other (OTH) AF: 0.578 AC: 16293 AN: 28196

GnomAD4 genome AF: 0.557 AC: 84619 AN: 151934 Hom.: 24108 Cov.: 32 AF XY: 0.563 AC XY: 41809 AN XY: 74256

African (AFR) AF: 0.470 AC: 19476 AN: 41432

American (AMR) AF: 0.637 AC: 9724 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1925 AN: 3468

East Asian (EAS) AF: 0.726 AC: 3724 AN: 5132

South Asian (SAS) AF: 0.694 AC: 3349 AN: 4824

European-Finnish (FIN) AF: 0.604 AC: 6373 AN: 10552

Middle Eastern (MID) AF: 0.500 AC: 147 AN: 294

European-Non Finnish (NFE) AF: 0.562 AC: 38171 AN: 67954

Other (OTH) AF: 0.596 AC: 1259 AN: 2112

Alfa AF: 0.564 Hom.: 31529

Bravo AF: 0.559

Asia WGS AF: 0.688 AC: 2391 AN: 3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cataplexy and narcolepsy Other:1

Dec 10, 2014

Center for Narcolepsy, Stanford University

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.38
PhyloP100		-0.27
PromoterAI		0.072	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12460842; hg19: chr19-10222195; COSMIC: COSV53452551; COSMIC: COSV53452551;