12-27647861-A-T

Position:

• chr12-27647861-A-T

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.490A>T​(p.Thr164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,598,116 control chromosomes in the GnomAD database, including 9 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 (8 hom.)
• Consequence: PPFIBP1 ENST00000535047.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.67

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=0.0057797134).
• BP6: Variant 12-27647861-A-T is Benign according to our data. Variant chr12-27647861-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 3025397.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-27647861-A-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00208 (316/152206) while in subpopulation NFE AF= 0.00279 (190/68018). AF 95% confidence interval is 0.00247. 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 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPFIBP1	NM_003622.4	c.471+19A>T		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+19A>T		intron_variant		1	NM_003622.4	ENSP00000228425.6

Frequencies

GnomAD3 genomes AF: 0.00208 AC: 316 AN: 152088 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.00128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00231

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000344 AC: 82 AN: 238082 Hom.: 0 AF XY: 0.000373 AC XY: 48 AN XY: 128818

Gnomad AFR exome AF: 0.000449

Gnomad AMR exome AF: 0.000322

Gnomad ASJ exome AF: 0.000208

Gnomad EAS exome AF: 0.000173

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.000374

Gnomad OTH exome AF: 0.000525

GnomAD4 exome AF: 0.00128 AC: 1847 AN: 1445910 Hom.: 8 Cov.: 35 AF XY: 0.00129 AC XY: 924 AN XY: 719058

Gnomad4 AFR exome AF: 0.000883

Gnomad4 AMR exome AF: 0.000800

Gnomad4 ASJ exome AF: 0.00202

Gnomad4 EAS exome AF: 0.000256

Gnomad4 SAS exome AF: 0.00127

Gnomad4 FIN exome AF: 0.00250

Gnomad4 NFE exome AF: 0.00126

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.00208 AC: 316 AN: 152206 Hom.: 1 Cov.: 31 AF XY: 0.00222 AC XY: 165 AN XY: 74408

Gnomad4 AFR AF: 0.00128

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00231

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000896 Hom.: 0

ExAC AF: 0.000148 AC: 18

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

Dec 01, 2023

PPFIBP1: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.0050
DANN	Benign	0.48
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.0	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.033
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0050	B
Vest4		0.10
MutPred		0.17		Gain of catalytic residue at P169 (P = 2e-04);
MVP		0.13
ClinPred		0.34	T
GERP RS		-4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs199881715; hg19: chr12-27800794;