15-55546288-T-A

Variant names:

Variant summary

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

The NM_001367806.1(PYGO1):c.995A>T(p.His332Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., 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: 2.35

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=0.110592246).

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.995A>T	p.His332Leu	missense_variant	Exon 3 of 3	ENST00000563719.4	NP_001354735.1
PYGO1	NM_001330326.2 link	c.995A>T	p.His332Leu	missense_variant	Exon 3 of 4		NP_001317255.1	Q9Y3Y4-2
PYGO1	NM_015617.3 link	c.995A>T	p.His332Leu	missense_variant	Exon 3 of 3		NP_056432.1	Q9Y3Y4-1
PYGO1	XM_047432381.1 link	c.680A>T	p.His227Leu	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.995A>T	p.His332Leu	missense_variant	Exon 3 of 3	5	NM_001367806.1	ENSP00000457777.1	Q9Y3Y4-2
PYGO1	ENST00000302000.10 link	c.995A>T	p.His332Leu	missense_variant	Exon 3 of 3	1		ENSP00000302327.6	Q9Y3Y4-1
PYGO1	ENST00000645724.1 link	c.995A>T	p.His332Leu	missense_variant	Exon 3 of 4			ENSP00000496139.1	Q9Y3Y4-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

249700

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134918

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

727240

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.995A>T (p.H332L) alteration is located in exon 3 (coding exon 3) of the PYGO1 gene. This alteration results from a A to T substitution at nucleotide position 995, causing the histidine (H) at amino acid position 332 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

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.092

T;.;.

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.77

T;.;T

M_CAP

Benign

0.0069

MetaRNN

Benign

0.11

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.0

N;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.19

T;.;T

Sift4G

Benign

0.79

T;.;T

Polyphen

0.0

B;.;.

Vest4

0.42

MutPred

0.14

Loss of catalytic residue at G333 (P = 0.1587);Loss of catalytic residue at G333 (P = 0.1587);Loss of catalytic residue at G333 (P = 0.1587);

MVP

0.47

MPC

0.43

ClinPred

0.26

GERP RS

2.9

Varity_R

0.13

gMVP

0.44

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