X-72181718-T-G

Variant names:

• chrX-72181718-T-G
• ENST00000664196.1:c.8T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001170747.1(PIN4):​c.8T>G​(p.Met3Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M3L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: PIN4 NM_001170747.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.108
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.113282055).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_001170747.1	c.8T>G	p.Met3Arg	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NM_006223.4	c.-68T>G		upstream_gene_variant		ENST00000373669.8	NP_006214.3
PIN4	NR_033187.2	n.-39T>G		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8	c.-68T>G		upstream_gene_variant		1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 30, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.8T>G (p.M3R) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a T to G substitution at nucleotide position 8, causing the methionine (M) at amino acid position 3 to be replaced by an arginine (R). 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	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.5
DANN	Benign	0.75
DEOGEN2	Benign	0.043	T;.;.
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.27	.;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.11
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.080	N;N;N
REVEL	Benign	0.014
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		0.0010	.;.;B
Vest4		0.25
MutPred		0.32		Gain of methylation at M3 (P = 0.0131);Gain of methylation at M3 (P = 0.0131);Gain of methylation at M3 (P = 0.0131);
MVP		0.068
MPC		0.16
ClinPred		0.83	D
GERP RS		1.0
PromoterAI		0.11	Neutral
gMVP		0.44
Mutation Taster		=94/6	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

hg19: chrX-71401568;