12-81268043-C-T

Position:

• chr12-81268043-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003625.5(PPFIA2):​c.3355G>A​(p.Ala1119Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00269 in 1,597,052 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (57 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (57 hom.)
• Consequence: PPFIA2 NM_003625.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.66

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006010115).
• BP6: Variant 12-81268043-C-T is Benign according to our data. Variant chr12-81268043-C-T is described in ClinVar as [Benign]. Clinvar id is 790120.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPFIA2	NM_003625.5	c.3355G>A	p.Ala1119Thr	missense_variant	29/33	ENST00000549396.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPFIA2	ENST00000549396.6	c.3355G>A	p.Ala1119Thr	missense_variant	29/33	1	NM_003625.5	A1

Frequencies

GnomAD3 genomes AF: 0.0146 AC: 2205 AN: 151392 Hom.: 57 Cov.: 30

Gnomad AFR AF: 0.0514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00408

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: 0.000177

Gnomad OTH AF: 0.00624

GnomAD3 exomes AF: 0.00343 AC: 784 AN: 228352 Hom.: 15 AF XY: 0.00262 AC XY: 323 AN XY: 123112

Gnomad AFR exome AF: 0.0507

Gnomad AMR exome AF: 0.00219

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000884

Gnomad OTH exome AF: 0.000704

GnomAD4 exome AF: 0.00144 AC: 2079 AN: 1445566 Hom.: 57 Cov.: 32 AF XY: 0.00120 AC XY: 858 AN XY: 717326

Gnomad4 AFR exome AF: 0.0522

Gnomad4 AMR exome AF: 0.00251

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000959

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000245

Gnomad4 OTH exome AF: 0.00339

GnomAD4 genome AF: 0.0146 AC: 2210 AN: 151486 Hom.: 57 Cov.: 30 AF XY: 0.0140 AC XY: 1034 AN XY: 73978

Gnomad4 AFR AF: 0.0514

Gnomad4 AMR AF: 0.00407

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00618

Alfa AF: 0.00192 Hom.: 10

Bravo AF: 0.0168

ESP6500AA AF: 0.0439 AC: 167

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00429 AC: 518

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 27, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	.;.;T;.;.;.;T;.;.;.;.
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;.;D
MetaRNN	Benign	0.0060	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.7	.;.;L;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.1	N;.;N;N;N;N;.;N;N;N;N
REVEL	Uncertain	0.43
Sift	Uncertain	0.0080	D;.;D;D;D;D;.;D;D;D;D
Sift4G	Uncertain	0.021	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.092	.;.;B;.;.;.;.;.;.;.;.
Vest4		0.37
MVP		0.61
MPC		1.1
ClinPred		0.034	T
GERP RS		5.9
Varity_R		0.38
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs56241008; hg19: chr12-81661822;