12-81263311-A-G

Variant names:

• chr12-81263311-A-G
• NM_003625.5:c.3635T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003625.5(PPFIA2):​c.3635T>C​(p.Met1212Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,288 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: 6.8e-7 (0 hom.)
• Consequence: PPFIA2 NM_003625.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.25

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32274622).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPFIA2	NM_003625.5	c.3635T>C	p.Met1212Thr	missense_variant	Exon 31 of 33	ENST00000549396.6	NP_003616.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPFIA2	ENST00000549396.6	c.3635T>C	p.Met1212Thr	missense_variant	Exon 31 of 33	1	NM_003625.5	ENSP00000450337.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460288 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726512

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	.;.;T;.;.;.;T;.;.;.;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D;D;D;D;D;D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;L;.;.;.;.;.;.;.;.
PROVEAN	Benign	-1.5	N;.;N;.;N;N;.;N;N;N;N
REVEL	Benign	0.21
Sift	Uncertain	0.0040	D;.;D;.;D;D;.;D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.16	.;.;B;.;.;.;.;.;.;.;.
Vest4		0.56
MutPred		0.23		.;.;Gain of glycosylation at M1212 (P = 0.0087);Gain of glycosylation at M1212 (P = 0.0087);.;.;.;.;.;.;.;
MVP		0.18
MPC		0.21
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.74
gMVP		0.39

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-81657090;