rs749947929

Variant names:

• chr12-81263335-C-T
• rs749947929
• NM_003625.5:c.3611G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_003625.5(PPFIA2):​c.3611G>A​(p.Arg1204His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,612,760 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (2 hom.)
• Consequence: PPFIA2 NM_003625.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.38
• Publications: 3 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28410065).
• BS2: High AC in GnomAdExome4 at 21 AD gene.

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.3611G>A	p.Arg1204His	missense	Exon 31 of 33	NP_003616.2
	PPFIA2	NM_001220476.2		c.3593G>A	p.Arg1198His	missense	Exon 30 of 32	NP_001207405.1	O75334-3
	PPFIA2	NM_001220473.3		c.3611G>A	p.Arg1204His	missense	Exon 30 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.3611G>A	p.Arg1204His	missense	Exon 31 of 33	ENSP00000450337.1	O75334-1
	PPFIA2	ENST00000548586.5	TSL:1	c.3593G>A	p.Arg1198His	missense	Exon 30 of 31	ENSP00000449338.1	O75334-3
	PPFIA2	ENST00000550584.6	TSL:1	c.3611G>A	p.Arg1204His	missense	Exon 30 of 31	ENSP00000449558.2	G3V200

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000201 AC: 5 AN: 248972 AF XY: 0.0000222

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: 0.0000464

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000144 AC: 21 AN: 1460652 Hom.: 2 Cov.: 30 AF XY: 0.0000234 AC XY: 17 AN XY: 726664

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26116

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39686

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86222

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000990 AC: 11 AN: 1110974

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.0000241 AC: 1 AN: 41412

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000331 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

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	Uncertain	0.43
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.4
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.16
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.29
MVP		0.48
MPC		0.79
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.29
Mutation Taster		=48/52	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: rs749947929; hg19: chr12-81657114; COSMIC: COSV61045208; COSMIC: COSV61045208;