rs61758740

Positions:

• chr1-154959577-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138300.4(PYGO2):​c.423G>A​(p.Met141Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,456,446 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (6 hom.)
• Consequence: PYGO2 NM_138300.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.30

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007651925).
• BS2: High AC in GnomAd4 at 412 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYGO2	NM_138300.4	c.423G>A	p.Met141Ile	missense_variant	3/3	ENST00000368457.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYGO2	ENST00000368457.3	c.423G>A	p.Met141Ile	missense_variant	3/3	1	NM_138300.4	P1
PYGO2	ENST00000368456.1	c.312G>A	p.Met104Ile	missense_variant	3/3	2

Frequencies

GnomAD3 genomes AF: 0.00273 AC: 414 AN: 151768 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00640

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.000839

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.00142 AC: 209 AN: 147278 Hom.: 1 AF XY: 0.00108 AC XY: 85 AN XY: 79060

Gnomad AFR exome AF: 0.00624

Gnomad AMR exome AF: 0.00311

Gnomad ASJ exome AF: 0.000775

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000873

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.00434

GnomAD4 exome AF: 0.000850 AC: 1109 AN: 1304560 Hom.: 6 Cov.: 29 AF XY: 0.000809 AC XY: 515 AN XY: 636288

Gnomad4 AFR exome AF: 0.00646

Gnomad4 AMR exome AF: 0.00393

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000147

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000648

Gnomad4 OTH exome AF: 0.00194

GnomAD4 genome AF: 0.00271 AC: 412 AN: 151886 Hom.: 1 Cov.: 32 AF XY: 0.00261 AC XY: 194 AN XY: 74214

Gnomad4 AFR AF: 0.00635

Gnomad4 AMR AF: 0.00459

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000839

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00195 Hom.: 1

Bravo AF: 0.00367

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00431 AC: 19

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00148 AC: 172

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.68	T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0077	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.19
Sift	Uncertain	0.029	D;D
Sift4G	Benign	0.40	T;T
Polyphen		0.0050	B;.
Vest4		0.34
MutPred		0.17		Loss of glycosylation at P140 (P = 0.0873);.;
MVP		0.64
MPC		0.30
ClinPred		0.012	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.40
gMVP		0.30

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: rs61758740; hg19: chr1-154932053;