X-72181801-A-G

Variant names:

• chrX-72181801-A-G
• rs2042674317
• NM_006223.4:c.16A>G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_006223.4(PIN4):​c.16A>G​(p.Lys6Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000014 in 1,070,708 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: PIN4 NM_006223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.79

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33774433).
• BS2: High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4	c.16A>G	p.Lys6Glu	missense_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3
PIN4	NM_001170747.1	c.91A>G	p.Lys31Glu	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NR_033187.2	n.45A>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIN4	ENST00000373669.8	c.16A>G	p.Lys6Glu	missense_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.0000140 AC: 15 AN: 1070708 Hom.: 0 Cov.: 27 AF XY: 0.0000148 AC XY: 5 AN XY: 338670

Gnomad4 AFR exome AF: 0.0000384

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: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.91A>G (p.K31E) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a A to G substitution at nucleotide position 91, causing the lysine (K) at amino acid position 31 to be replaced by a glutamic acid (E). 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	Uncertain	0.41
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.17	T;.;.;T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.72	.;T;T;.
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.34	T;T;T;T
MetaSVM	Benign	-0.29	T
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0040	D;D;D;D
Sift4G	Uncertain	0.047	D;D;D;D
Polyphen		1.0	.;.;D;.
Vest4		0.35
MutPred		0.28		Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);Loss of MoRF binding (P = 0.0068);.;
MVP		0.59
MPC		0.34
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs2042674317; hg19: chrX-71401651;