19-49130418-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003660.4(PPFIA3):c.698G>C(p.Arg233Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R233Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PPFIA3 NM_003660.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.34

Genes affected

PPFIA3 (HGNC:9247): (PTPRF interacting protein alpha 3) 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. Liprin family protein has been shown to localize phosphatase LAR to cell focal adhesions and may be involved in the molecular organization of presynaptic active zones. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, PPFIA3
• BP4: Computational evidence support a benign effect (MetaRNN=0.3947246).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPFIA3	NM_003660.4	c.698G>C	p.Arg233Pro	missense_variant	7/30	ENST00000334186.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPFIA3	ENST00000334186.9	c.698G>C	p.Arg233Pro	missense_variant	7/30	1	NM_003660.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 07, 2021

The c.698G>C (p.R233P) alteration is located in exon 7 (coding exon 6) of the PPFIA3 gene. This alteration results from a G to C substitution at nucleotide position 698, causing the arginine (R) at amino acid position 233 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0072	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.39	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.60	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.22
Sift	Benign	0.18	T;.
Sift4G	Benign	0.21	T;T
Polyphen		0.18	B;P
Vest4		0.66
MutPred		0.15		Loss of methylation at R233 (P = 0.0991);Loss of methylation at R233 (P = 0.0991);
MVP		0.48
MPC		0.82
ClinPred		0.90	D
GERP RS		4.2
Varity_R		0.55
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr19-49633675;