15-55546318-C-G

Position:

• chr15-55546318-C-G

Variant summary

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

The NM_001367806.1(PYGO1):​c.965G>C​(p.Ser322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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)
• Consequence: PYGO1 NM_001367806.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.00

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]

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=0.08429703).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYGO1	NM_001367806.1	c.965G>C	p.Ser322Thr	missense_variant	3/3	ENST00000563719.4	NP_001354735.1
PYGO1	NM_001330326.2	c.965G>C	p.Ser322Thr	missense_variant	3/4		NP_001317255.1
PYGO1	NM_015617.3	c.965G>C	p.Ser322Thr	missense_variant	3/3		NP_056432.1
PYGO1	XM_047432381.1	c.650G>C	p.Ser217Thr	missense_variant	3/3		XP_047288337.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYGO1	ENST00000563719.4	c.965G>C	p.Ser322Thr	missense_variant	3/3	5	NM_001367806.1	ENSP00000457777.1
PYGO1	ENST00000302000.10	c.965G>C	p.Ser322Thr	missense_variant	3/3	1		ENSP00000302327.6
PYGO1	ENST00000645724.1	c.965G>C	p.Ser322Thr	missense_variant	3/4			ENSP00000496139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 25, 2024

The c.965G>C (p.S322T) alteration is located in exon 3 (coding exon 3) of the PYGO1 gene. This alteration results from a G to C substitution at nucleotide position 965, causing the serine (S) at amino acid position 322 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	0.082
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.082	T;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.031
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.57	T;.;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.084	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.79	N;.;N
REVEL	Benign	0.064
Sift	Benign	0.94	T;.;T
Sift4G	Benign	0.88	T;.;T
Polyphen		0.079	B;.;.
Vest4		0.34
MutPred		0.13		Loss of phosphorylation at T319 (P = 0.1042);Loss of phosphorylation at T319 (P = 0.1042);Loss of phosphorylation at T319 (P = 0.1042);
MVP		0.34
MPC		0.13
ClinPred		0.44	T
GERP RS		4.3
Varity_R		0.16
gMVP		0.46

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-55838516;