X-72197476-G-A

Position:

• chrX-72197476-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006223.4(PIN4):​c.346G>A​(p.Val116Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000183 in 1,093,656 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. 12/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 2 hem.)
• Consequence: PIN4 NM_006223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.59

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

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19652441).
• BS2: High Hemizygotes in GnomAdExome4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIN4	NM_006223.4	c.346G>A	p.Val116Ile	missense_variant	4/4	ENST00000373669.8	NP_006214.3
PIN4	NM_001170747.1	c.312+572G>A		intron_variant			NP_001164218.1
PIN4	NR_033187.2	n.301G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8	c.346G>A	p.Val116Ile	missense_variant	4/4	1	NM_006223.4	ENSP00000362773	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000183 AC: 2 AN: 1093656 Hom.: 0 Cov.: 27 AF XY: 0.00000557 AC XY: 2 AN XY: 359130

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 23

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

Sep 14, 2023

The c.421G>A (p.V141I) alteration is located in exon 4 (coding exon 4) of the PIN4 gene. This alteration results from a G to A substitution at nucleotide position 421, causing the valine (V) at amino acid position 141 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
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.91
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.086
Sift	Benign	0.16	T
Sift4G	Benign	0.20	T
Polyphen		0.068	B
Vest4		0.27
MutPred		0.76		Loss of disorder (P = 0.1587);
MVP		0.15
MPC		0.097
ClinPred		0.28	T
GERP RS		2.6
gMVP		0.43

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-71417326;