chrX-72181765-G-C

Variant names:

• chrX-72181765-G-C
• rs769563285
• NM_006223.4:c.-21G>C

Variant summary

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

The NM_006223.4(PIN4):​c.-21G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000893 in 112,006 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: PIN4 NM_006223.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.734
• 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=0.16732708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIN4	NM_006223.4	c.-21G>C		5_prime_UTR_variant	Exon 1 of 4	ENST00000373669.8	NP_006214.3
PIN4	NM_001170747.1	c.55G>C	p.Val19Leu	missense_variant	Exon 1 of 4		NP_001164218.1
PIN4	NR_033187.2	n.9G>C		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.-21G>C		5_prime_UTR_variant	Exon 1 of 4	1	NM_006223.4	ENSP00000362773.3

Frequencies

GnomAD3 genomes AF: 0.00000893 AC: 1 AN: 112006 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000280

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: 0.00000548 AC: 1 AN: 182439 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000276 AC: 3 AN: 1085604 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 352736

African (AFR) AF: 0.00 AC: 0 AN: 26232

American (AMR) AF: 0.00 AC: 0 AN: 35175

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19308

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30182

South Asian (SAS) AF: 0.0000186 AC: 1 AN: 53789

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3359

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831411

Other (OTH) AF: 0.0000219 AC: 1 AN: 45634

GnomAD4 genome AF: 0.00000893 AC: 1 AN: 112006 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34170

African (AFR) AF: 0.00 AC: 0 AN: 30746

American (AMR) AF: 0.00 AC: 0 AN: 10578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000280 AC: 1 AN: 3571

South Asian (SAS) AF: 0.00 AC: 0 AN: 2734

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6089

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 240

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53202

Other (OTH) AF: 0.00 AC: 0 AN: 1505

Alfa AF: 0.00 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

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.55G>C (p.V19L) alteration is located in exon 1 (coding exon 1) of the PIN4 gene. This alteration results from a G to C substitution at nucleotide position 55, causing the valine (V) at amino acid position 19 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	-0.38	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.3
DANN	Benign	0.89
DEOGEN2	Benign	0.055	T;.;.;T
FATHMM_MKL	Benign	0.47	N
LIST_S2	Benign	0.57	.;T;T;.
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-0.99	T
PhyloP100		0.73
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.23	N;N;N;N
REVEL	Benign	0.019
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Benign	0.094	T;D;T;D
Polyphen		0.064	.;.;B;.
Vest4		0.26
MutPred		0.24		Loss of catalytic residue at V19 (P = 0.1143);Loss of catalytic residue at V19 (P = 0.1143);Loss of catalytic residue at V19 (P = 0.1143);.;
MVP		0.23
MPC		0.11
ClinPred		0.38	T
GERP RS		3.1
PromoterAI		-0.0035	Neutral
gMVP		0.22
Mutation Taster		=98/2	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: rs769563285; hg19: chrX-71401615;