1-154959315-T-C

Variant names:

• chr1-154959315-T-C
• rs1655267929
• NM_138300.4:c.685A>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138300.4(PYGO2):​c.685A>G​(p.Arg229Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,606 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PYGO2 NM_138300.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

Genes affected

PYGO2 (HGNC:30257): (pygopus family PHD finger 2) Predicted to enable several functions, including chromatin binding activity; histone acetyltransferase regulator activity; and histone binding activity. Predicted to be involved in kidney development and spermatid nucleus differentiation. Predicted to act upstream of or within several processes, including animal organ development; positive regulation of chromatin binding activity; and regulation of histone H3-K4 methylation. Part of beta-catenin-TCF complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24598023).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYGO2	NM_138300.4	c.685A>G	p.Arg229Gly	missense_variant	Exon 3 of 3	ENST00000368457.3	NP_612157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYGO2	ENST00000368457.3	c.685A>G	p.Arg229Gly	missense_variant	Exon 3 of 3	1	NM_138300.4	ENSP00000357442.2
PYGO2	ENST00000368456.1	c.574A>G	p.Arg192Gly	missense_variant	Exon 3 of 3	2		ENSP00000357441.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1449606 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 720832

Gnomad4 AFR exome AF: 0.0000607

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 19, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685A>G (p.R229G) alteration is located in exon 3 (coding exon 3) of the PYGO2 gene. This alteration results from a A to G substitution at nucleotide position 685, causing the arginine (R) at amino acid position 229 to be replaced by a glycine (G). 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	0.20
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.055
Eigen_PC	Benign	0.062
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0093	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.25
Sift	Benign	0.39	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.78	P;.
Vest4		0.55
MutPred		0.21		Gain of glycosylation at P224 (P = 0.1453);.;
MVP		0.80
MPC		0.64
ClinPred		0.31	T
GERP RS		3.6
Varity_R		0.094
gMVP		0.56

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

Other links and lift over

dbSNP: rs1655267929; hg19: chr1-154931791;