Genetic Variant PYGO1:p.Arg125Lys (chr15-55546909-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001367806.1(PYGO1):c.374G>A(p.Arg125Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000178 in 1,461,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

PYGO1
NM_001367806.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.27248704).

BS2

High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO1	NM_001367806.1 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 3	ENST00000563719.4	NP_001354735.1
PYGO1	NM_001330326.2 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 4		NP_001317255.1	Q9Y3Y4-2
PYGO1	NM_015617.3 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 3		NP_056432.1	Q9Y3Y4-1
PYGO1	XM_047432381.1 link	c.59G>A	p.Arg20Lys	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.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 3	5	NM_001367806.1	ENSP00000457777.1	Q9Y3Y4-2
PYGO1	ENST00000302000.10 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 3	1		ENSP00000302327.6	Q9Y3Y4-1
PYGO1	ENST00000645724.1 link	c.374G>A	p.Arg125Lys	missense_variant	Exon 3 of 4			ENSP00000496139.1	Q9Y3Y4-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251250

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135774

show subpopulations

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 SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727228

show subpopulations

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000468

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 22, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374G>A (p.R125K) alteration is located in exon 3 (coding exon 3) of the PYGO1 gene. This alteration results from a G to A substitution at nucleotide position 374, causing the arginine (R) at amino acid position 125 to be replaced by a lysine (K). 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

0.34

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.;.

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;.;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.27

T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.2

M;M;M

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.96

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.035

D;.;D

Sift4G

Benign

0.35

T;.;T

Polyphen

0.98

D;.;.

Vest4

0.53

MutPred

0.26

Gain of ubiquitination at R125 (P = 0.0082);Gain of ubiquitination at R125 (P = 0.0082);Gain of ubiquitination at R125 (P = 0.0082);

MVP

0.44

MPC

0.53

ClinPred

0.63

GERP RS

5.1

Varity_R

0.31

gMVP

0.68

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

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