12-27655167-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000318304.12(PPFIBP1):c.721A>T(p.Met241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,300 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. M241I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: PPFIBP1 ENST00000318304.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.76

Genes affected

PPFIBP1 (HGNC:9249): (PPFIA binding protein 1) 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 was found to interact with S100A4, a calcium-binding protein related to tumor invasiveness and metastasis. In vitro experiment demonstrated that the interaction inhibited the phosphorylation of this protein by protein kinase C and protein kinase CK2. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.071596).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PPFIBP1	NM_003622.4	c.696+353A>T		intron_variant		ENST00000228425.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PPFIBP1	ENST00000228425.11	c.696+353A>T		intron_variant		1	NM_003622.4	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000216 AC: 3 AN: 138852 Hom.: 0 AF XY: 0.0000401 AC XY: 3 AN XY: 74898

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383300 Hom.: 0 Cov.: 30 AF XY: 0.00000439 AC XY: 3 AN XY: 682642

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000841

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Mar 31, 2023

The c.721A>T (p.M241L) alteration is located in exon 9 (coding exon 7) of the PPFIBP1 gene. This alteration results from a A to T substitution at nucleotide position 721, causing the methionine (M) at amino acid position 241 to be replaced by a leucine (L). 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	0.20
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.43
Cadd	Benign	23
Dann	Benign	0.79
DEOGEN2	Benign	0.0030	T;.;T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.072	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.25	N;N;N
REVEL	Benign	0.062
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0080, 0.0020	.;B;B
Vest4		0.19, 0.19
MutPred		0.20		.;.;Loss of stability (P = 0.0482);
MVP		0.18
MPC		0.31
ClinPred		0.20	T
GERP RS		4.9
Varity_R		0.35
gMVP		0.19

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1159614180; hg19: chr12-27808100;