rs764492966

Variant names:

• chr12-81267986-G-C
• rs764492966
• NM_003625.5:c.3412C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003625.5(PPFIA2):​c.3412C>G​(p.Leu1138Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 151,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000020 (0 hom., cov: 30)
• Consequence: PPFIA2 NM_003625.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• Publications: 0 publications found

Genes affected

PPFIA2 (HGNC:9246): (PTPRF interacting protein alpha 2) The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein has been shown to bind the calcium/calmodulin-dependent serine protein kinase (MAGUK family) protein (also known as CASK) and proposed to regulate higher-order brain functions in mammals. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

PPFIA2 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003625.5. 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
	PPFIA2	NM_003625.5	MANE Select	c.3412C>G	p.Leu1138Val	missense	Exon 29 of 33	NP_003616.2
	PPFIA2	NM_001220476.2		c.3394C>G	p.Leu1132Val	missense	Exon 28 of 32	NP_001207405.1	O75334-3
	PPFIA2	NM_001220473.3		c.3412C>G	p.Leu1138Val	missense	Exon 28 of 31	NP_001207402.1	G3V200

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PPFIA2	ENST00000549396.6	TSL:1 MANE Select	c.3412C>G	p.Leu1138Val	missense	Exon 29 of 33	ENSP00000450337.1	O75334-1
	PPFIA2	ENST00000548586.5	TSL:1	c.3394C>G	p.Leu1132Val	missense	Exon 28 of 31	ENSP00000449338.1	O75334-3
	PPFIA2	ENST00000550584.6	TSL:1	c.3412C>G	p.Leu1138Val	missense	Exon 28 of 31	ENSP00000449558.2	G3V200

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151974 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151974 Hom.: 0 Cov.: 30 AF XY: 0.0000135 AC XY: 1 AN XY: 74208

African (AFR) AF: 0.00 AC: 0 AN: 41386

American (AMR) AF: 0.000197 AC: 3 AN: 15262

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

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10550

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.045	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		10
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.62
Sift	Benign	0.26	T
Sift4G	Benign	0.11	T
Polyphen		0.97	D
Vest4		0.66
MutPred		0.47		Gain of sheet (P = 0.0827)
MVP		0.72
MPC		1.6
ClinPred		0.57	D
GERP RS		5.9
Varity_R		0.71
gMVP		0.57
Mutation Taster		=44/56	disease causing

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: rs764492966; hg19: chr12-81661765;