1-158942198-A-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_152501.5(PYHIN1):c.801A>T(p.Arg267Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,614,010 control chromosomes in the GnomAD database, including 4 homozygotes. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R267G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00063 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (3 hom.)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -6.92

Genes affected

PYHIN1 (HGNC:28894): (pyrin and HIN domain family member 1) The protein encoded by this gene belongs to the HIN-200 family of interferon-inducible proteins that share a 200-amino acid signature motif at their C-termini. HIN200 proteins are primarily nuclear and are involved in transcriptional regulation of genes important for cell cycle control, differentiation, and apoptosis. Downregulation of this gene is associated with breast cancer. This protein acts as a tumor suppressor by promoting ubiquitination and subsequent degradation of MDM2, which leads to stabilization of p53/TP53. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013433933).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYHIN1	NM_152501.5	c.801A>T	p.Arg267Ser	missense_variant	5/9	ENST00000368140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYHIN1	ENST00000368140.6	c.801A>T	p.Arg267Ser	missense_variant	5/9	1	NM_152501.5	P2

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000737 AC: 185 AN: 250948 Hom.: 0 AF XY: 0.000752 AC XY: 102 AN XY: 135688

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00177

Gnomad FIN exome AF: 0.000509

Gnomad NFE exome AF: 0.000846

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.00104 AC: 1526 AN: 1461680 Hom.: 3 Cov.: 31 AF XY: 0.00105 AC XY: 763 AN XY: 727130

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00163

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.000911

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152330 Hom.: 1 Cov.: 32 AF XY: 0.000631 AC XY: 47 AN XY: 74488

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000822 Hom.: 0

Bravo AF: 0.000597

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000758 AC: 92

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00125

EpiControl AF: 0.00101

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

Jul 06, 2021

The c.801A>T (p.R267S) alteration is located in exon 5 (coding exon 4) of the PYHIN1 gene. This alteration results from a A to T substitution at nucleotide position 801, causing the arginine (R) at amino acid position 267 to be replaced by a serine (S). 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	Uncertain	0.44
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	0.19
Dann	Benign	0.76
DEOGEN2	Benign	0.013	T;.;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0012	N
LIST_S2	Benign	0.79	T;T;T;T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.4	L;.;L;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.036
Sift	Uncertain	0.0060	D;D;D;D
Sift4G	Uncertain	0.010	D;D;D;D
Polyphen		0.24	B;B;B;B
Vest4		0.32
MutPred		0.64		Gain of phosphorylation at R267 (P = 0.0477);.;Gain of phosphorylation at R267 (P = 0.0477);.;
MVP		0.048
MPC		0.20
ClinPred		0.014	T
GERP RS		-5.7
Varity_R		0.13
gMVP		0.069

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs142992506; hg19: chr1-158911988;