rs1225770176

Variant names:

• chrX-72181741-G-A
• rs1225770176
• ENST00000664196.1:c.31G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001170747.1(PIN4):​c.31G>A​(p.Val11Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000594 in 1,179,404 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 24)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: PIN4 NM_001170747.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.05
• Publications: 0 publications found

Genes affected

PIN4 (HGNC:8992): (peptidylprolyl cis/trans isomerase, NIMA-interacting 4) This gene encodes a member of the parvulin subfamily of the peptidyl-prolyl cis/trans isomerase protein family. The encoded protein catalyzes the isomerization of peptidylprolyl bonds, and may play a role in the cell cycle, chromatin remodeling, and/or ribosome biogenesis. The encoded protein may play an additional role in the mitochondria. [provided by RefSeq, Dec 2009]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08749029).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1	c.31G>A	p.Val11Ile	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NM_006223.4	c.-45G>A		upstream_gene_variant		ENST00000373669.8	NP_006214.3
PIN4	NR_033187.2	n.-16G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8	c.-45G>A		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112251 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000972

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000547 AC: 1 AN: 182837 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000375 AC: 4 AN: 1067153 Hom.: 0 Cov.: 24 AF XY: 0.00000295 AC XY: 1 AN XY: 338779

African (AFR) AF: 0.00 AC: 0 AN: 26041

American (AMR) AF: 0.00 AC: 0 AN: 35174

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19200

East Asian (EAS) AF: 0.00 AC: 0 AN: 30156

South Asian (SAS) AF: 0.00 AC: 0 AN: 53571

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3047

European-Non Finnish (NFE) AF: 0.00000491 AC: 4 AN: 814340

Other (OTH) AF: 0.00 AC: 0 AN: 45103

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112251 Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1 AN XY: 34409

African (AFR) AF: 0.0000972 AC: 3 AN: 30862

American (AMR) AF: 0.00 AC: 0 AN: 10632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3581

South Asian (SAS) AF: 0.00 AC: 0 AN: 2758

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53250

Other (OTH) AF: 0.00 AC: 0 AN: 1512

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.31G>A (p.V11I) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a G to A substitution at nucleotide position 31, causing the valine (V) at amino acid position 11 to be replaced by an isoleucine (I). 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	-0.45	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	10
DANN	Benign	0.72
DEOGEN2	Benign	0.043	T;.;.
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.38	.;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.1
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.020	N;N;N
REVEL	Benign	0.053
Sift	Uncertain	0.025	D;D;D
Sift4G	Benign	0.52	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.17
MutPred		0.38		Loss of ubiquitination at K8 (P = 0.1264);Loss of ubiquitination at K8 (P = 0.1264);Loss of ubiquitination at K8 (P = 0.1264);
MVP		0.10
MPC		0.086
ClinPred		0.031	T
GERP RS		1.9
PromoterAI		-0.064	Neutral
gMVP		0.22
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1225770176; hg19: chrX-71401591;