Genetic Variant PYGO1:p.Pro237Thr (chr15-55546574-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001367806.1(PYGO1):c.709C>A(p.Pro237Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 0 hom. )

Consequence

PYGO1
NM_001367806.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.44

Variant links:

Genes affected

PYGO1 (HGNC:30256): (pygopus family PHD finger 1) Enables methylated histone binding activity. Predicted to be involved in kidney development and spermatid nucleus differentiation. Predicted to act upstream of or within several processes, including hematopoietic progenitor cell differentiation; protein localization to nucleus; and spermatid development. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

PYGO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.085050285).

BS2

High AC in GnomAd4 at 31 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO1	NM_001367806.1 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 3	ENST00000563719.4	NP_001354735.1
PYGO1	NM_001330326.2 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 4		NP_001317255.1	Q9Y3Y4-2
PYGO1	NM_015617.3 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 3		NP_056432.1	Q9Y3Y4-1
PYGO1	XM_047432381.1 link	c.394C>A	p.Pro132Thr	missense_variant	Exon 3 of 3		XP_047288337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PYGO1	ENST00000563719.4 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 3	5	NM_001367806.1	ENSP00000457777.1	Q9Y3Y4-2
PYGO1	ENST00000302000.10 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 3	1		ENSP00000302327.6	Q9Y3Y4-1
PYGO1	ENST00000645724.1 link	c.709C>A	p.Pro237Thr	missense_variant	Exon 3 of 4			ENSP00000496139.1	Q9Y3Y4-2

Frequencies

GnomAD3 genomes

AF:

0.000204

AC:

AN:

152028

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000200

AC:

AN:

250354

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.0000639

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000231

Gnomad NFE exome

AF:

0.000353

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

196

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000300

Gnomad4 NFE exome

AF:

0.000313

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000204

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000229

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.000206

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.709C>A (p.P237T) alteration is located in exon 3 (coding exon 3) of the PYGO1 gene. This alteration results from a C to A substitution at nucleotide position 709, causing the proline (P) at amino acid position 237 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

0.063

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.15

T;.;.

Eigen

Benign

-0.093

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.76

T;.;T

M_CAP

Benign

0.0081

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N;N

PrimateAI

Benign

0.36

PROVEAN

Uncertain

-2.4

N;.;N

REVEL

Benign

0.034

Sift

Uncertain

0.014

D;.;D

Sift4G

Uncertain

0.026

D;.;D

Polyphen

0.0040

B;.;.

Vest4

0.17

MVP

0.21

MPC

0.14

ClinPred

0.039

GERP RS

5.0

Varity_R

0.14

gMVP

0.45

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over