12-27647854-G-C

Position:

• chr12-27647854-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000535047.5(PPFIBP1):​c.483G>C​(p.Glu161Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,601,324 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0013 (6 hom.)
• Consequence: PPFIBP1 ENST00000535047.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.365

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011700124).
• BP6: Variant 12-27647854-G-C is Benign according to our data. Variant chr12-27647854-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3388297.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-27647854-G-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00206 (313/152192) while in subpopulation NFE AF= 0.0027 (184/68024). AF 95% confidence interval is 0.00239. There are 1 homozygotes in gnomad4. There are 165 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPFIBP1	NM_003622.4	c.471+12G>C		intron_variant		ENST00000228425.11	NP_003613.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPFIBP1	ENST00000228425.11	c.471+12G>C		intron_variant		1	NM_003622.4	ENSP00000228425.6

Frequencies

GnomAD3 genomes AF: 0.00206 AC: 313 AN: 152074 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00425

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00270

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000431 AC: 104 AN: 241576 Hom.: 0 AF XY: 0.000398 AC XY: 52 AN XY: 130648

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.000282

Gnomad ASJ exome AF: 0.000203

Gnomad EAS exome AF: 0.00125

Gnomad SAS exome AF: 0.000208

Gnomad FIN exome AF: 0.000377

Gnomad NFE exome AF: 0.000425

Gnomad OTH exome AF: 0.000518

GnomAD4 exome AF: 0.00126 AC: 1828 AN: 1449132 Hom.: 6 Cov.: 35 AF XY: 0.00125 AC XY: 903 AN XY: 720686

Gnomad4 AFR exome AF: 0.000849

Gnomad4 AMR exome AF: 0.000812

Gnomad4 ASJ exome AF: 0.00205

Gnomad4 EAS exome AF: 0.000613

Gnomad4 SAS exome AF: 0.00105

Gnomad4 FIN exome AF: 0.00315

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00128

GnomAD4 genome AF: 0.00206 AC: 313 AN: 152192 Hom.: 1 Cov.: 31 AF XY: 0.00222 AC XY: 165 AN XY: 74412

Gnomad4 AFR AF: 0.00123

Gnomad4 AMR AF: 0.000785

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.000965

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00425

Gnomad4 NFE AF: 0.00270

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00182

ExAC AF: 0.000478 AC: 58

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Oct 01, 2024

PPFIBP1: BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.56
DANN	Benign	0.90
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.22	T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.0040
Sift	Benign	0.080	T
Sift4G	Benign	0.28	T
Polyphen		0.0090	B
Vest4		0.15
MutPred		0.17		Loss of disorder (P = 0.0627);
MVP		0.22
ClinPred		0.0014	T
GERP RS		-0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs200193700; hg19: chr12-27800787;