1-203053766-C-T

Position:

• chr1-203053766-C-T

Variant summary

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

The NM_001304331.2(PPFIA4):​c.1634C>T​(p.Ser545Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,398,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/16 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. S545C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: PPFIA4 NM_001304331.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.19

Genes affected

PPFIA4 (HGNC:9248): (PTPRF interacting protein alpha 4) PPFIA4, or liprin-alpha-4, belongs to the liprin-alpha gene family. See liprin-alpha-1 (LIP1, or PPFIA1; MIM 611054) for background on liprins.[supplied by OMIM, Mar 2008]

PPFIA4 (HGNC:):

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=0.2111626).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PPFIA4	NM_001304331.2	c.1634C>T	p.Ser545Phe	missense_variant	15/30	ENST00000295706.9	NP_001291260.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PPFIA4	ENST00000295706.9	c.1634C>T	p.Ser545Phe	missense_variant	15/30	5	NM_001304331.2	ENSP00000295706.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1398594 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689856

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 29, 2024

The c.116C>T (p.S39F) alteration is located in exon 2 (coding exon 2) of the PPFIA4 gene. This alteration results from a C to T substitution at nucleotide position 116, causing the serine (S) at amino acid position 39 to be replaced by a phenylalanine (F). 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
BayesDel_addAF	Benign	-0.092	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.025	T;.;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.90	D;D;D;.
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.69	T
PROVEAN	Benign	-1.9	N;N;N;.
REVEL	Benign	0.062
Sift	Benign	0.053	T;D;D;.
Sift4G	Uncertain	0.044	D;T;T;T
Polyphen		0.28	.;B;.;B
Vest4		0.36
MVP		0.63
MPC		0.53
ClinPred		0.31	T
GERP RS		5.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1273677518; hg19: chr1-203022894;