X-72181819-G-A

Variant names:

• chrX-72181819-G-A
• rs1274971838
• NM_006223.4:c.34G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006223.4(PIN4):​c.34G>A​(p.Ala12Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000061 in 1,147,302 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. 14/18 in silico tools predict 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: 0.0000058 (0 hom. 5 hem.)
• Consequence: PIN4 NM_006223.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1028218).
• 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.34G>A	p.Ala12Thr	missense_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3
PIN4	NM_001170747.1	c.109G>A	p.Ala37Thr	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NR_033187.2	n.63G>A		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.34G>A	p.Ala12Thr	missense_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112122 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

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: 0.000664

GnomAD2 exomes AF: 0.00000620 AC: 1 AN: 161228 AF XY: 0.0000198

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: 0.0000145

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000580 AC: 6 AN: 1035180 Hom.: 0 Cov.: 24 AF XY: 0.0000161 AC XY: 5 AN XY: 309726

African (AFR) AF: 0.00 AC: 0 AN: 25553

American (AMR) AF: 0.00 AC: 0 AN: 33798

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18867

East Asian (EAS) AF: 0.00 AC: 0 AN: 29879

South Asian (SAS) AF: 0.00 AC: 0 AN: 51546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39941

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3822

European-Non Finnish (NFE) AF: 0.00000762 AC: 6 AN: 787714

Other (OTH) AF: 0.00 AC: 0 AN: 44060

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112122 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34284

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30819

American (AMR) AF: 0.00 AC: 0 AN: 10603

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3558

South Asian (SAS) AF: 0.00 AC: 0 AN: 2738

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6082

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53252

Other (OTH) AF: 0.000664 AC: 1 AN: 1506

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.109G>A (p.A37T) 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 109, causing the alanine (A) at amino acid position 37 to be replaced by a threonine (T). 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	0.076
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Benign	0.049	T;.;.;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.37	.;T;T;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.10	T;T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.77	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.027	.;.;B;.
Vest4		0.16
MVP		0.31
MPC		0.11
ClinPred		0.20	T
GERP RS		4.2
PromoterAI		0.11	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.37
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1274971838; hg19: chrX-71401669;