NM_003625.5:c.2604C>T

Variant names:

• chr12-81325815-G-A
• rs368047640
• NM_003625.5:c.2604C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_003625.5(PPFIA2):​c.2604C>T​(p.Leu868Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000062 in 1,612,618 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (1 hom.)
• Consequence: PPFIA2 NM_003625.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.240
• Publications: 1 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.028).
• BP6: Variant 12-81325815-G-A is Benign according to our data. Variant chr12-81325815-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2643199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.24 with no splicing effect.
• BS2: High AC in GnomAd4 at 5 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.2604C>T	p.Leu868Leu	synonymous	Exon 22 of 33	NP_003616.2
	PPFIA2	NM_001220476.2		c.2604C>T	p.Leu868Leu	synonymous	Exon 21 of 32	NP_001207405.1	O75334-3
	PPFIA2	NM_001220473.3		c.2604C>T	p.Leu868Leu	synonymous	Exon 21 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.2604C>T	p.Leu868Leu	synonymous	Exon 22 of 33	ENSP00000450337.1	O75334-1
	PPFIA2	ENST00000548586.5	TSL:1	c.2604C>T	p.Leu868Leu	synonymous	Exon 21 of 31	ENSP00000449338.1	O75334-3
	PPFIA2	ENST00000550584.6	TSL:1	c.2604C>T	p.Leu868Leu	synonymous	Exon 21 of 31	ENSP00000449558.2	G3V200

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 151954 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000416

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000764 AC: 19 AN: 248778 AF XY: 0.0000963

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: 0.0000444

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000650 AC: 95 AN: 1460546 Hom.: 1 Cov.: 30 AF XY: 0.0000826 AC XY: 60 AN XY: 726564

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.000452 AC: 39 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111066

Other (OTH) AF: 0.000182 AC: 11 AN: 60308

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000416 AC: 2 AN: 4806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000833 Hom.: 0

Bravo AF: 0.0000453

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	8.0
DANN	Benign	0.72
PhyloP100		0.24
PromoterAI		-0.035	Neutral
Mutation Taster		=98/2	polymorphism

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: rs368047640; hg19: chr12-81719594; COSMIC: COSV61022750; COSMIC: COSV61022750;