X-72181717-A-T

Variant names:

• chrX-72181717-A-T
• rs764405239
• ENST00000218432.10:c.-69A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000218432.10(PIN4):​c.-69A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,095,271 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.0000051 (0 hom. 1 hem.)
• Consequence: PIN4 ENST00000218432.10 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.20
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05900967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1	c.7A>T	p.Met3Leu	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NM_006223.4	c.-69A>T		upstream_gene_variant		ENST00000373669.8	NP_006214.3
PIN4	NR_033187.2	n.-40A>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8	c.-69A>T		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes AF: 0.00000888 AC: 1 AN: 112572 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000939

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: 0.0000164 AC: 3 AN: 182767 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000509 AC: 5 AN: 982699 Hom.: 0 Cov.: 20 AF XY: 0.00000343 AC XY: 1 AN XY: 291311

African (AFR) AF: 0.00 AC: 0 AN: 25021

American (AMR) AF: 0.000143 AC: 5 AN: 35077

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18667

East Asian (EAS) AF: 0.00 AC: 0 AN: 29962

South Asian (SAS) AF: 0.00 AC: 0 AN: 52163

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40481

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2732

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 736194

Other (OTH) AF: 0.00 AC: 0 AN: 42402

GnomAD4 genome AF: 0.00000888 AC: 1 AN: 112572 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34700

African (AFR) AF: 0.00 AC: 0 AN: 30943

American (AMR) AF: 0.0000939 AC: 1 AN: 10650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

East Asian (EAS) AF: 0.00 AC: 0 AN: 3605

South Asian (SAS) AF: 0.00 AC: 0 AN: 2779

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6141

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53355

Other (OTH) AF: 0.00 AC: 0 AN: 1516

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7A>T (p.M3L) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a A to T substitution at nucleotide position 7, causing the methionine (M) at amino acid position 3 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
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.020
DANN	Benign	0.70
DEOGEN2	Benign	0.043	T;.;.
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.28	.;T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.059	T;T;T
MetaSVM	Benign	-0.95	T
PhyloP100		-1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.020	N;N;N
REVEL	Benign	0.024
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	.;.;B
Vest4		0.12
MutPred		0.30		Loss of MoRF binding (P = 0.1049);Loss of MoRF binding (P = 0.1049);Loss of MoRF binding (P = 0.1049);
MVP		0.12
MPC		0.098
ClinPred		0.10	T
GERP RS		-8.3
PromoterAI		-0.32	Neutral
gMVP		0.26
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: rs764405239; hg19: chrX-71401567;