1-158939091-A-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152501.5(PYHIN1):c.423A>C(p.Lys141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000522 in 1,581,564 control chromosomes in the GnomAD database, including 1 homozygotes. 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: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (1 hom.)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.44

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021538556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYHIN1	NM_152501.5	c.423A>C	p.Lys141Asn	missense_variant	4/9	ENST00000368140.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYHIN1	ENST00000368140.6	c.423A>C	p.Lys141Asn	missense_variant	4/9	1	NM_152501.5	P2

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000145

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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000676

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000411 AC: 91 AN: 221564 Hom.: 0 AF XY: 0.000358 AC XY: 43 AN XY: 120134

Gnomad AFR exome AF: 0.0000637

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: 0.000530

Gnomad NFE exome AF: 0.000748

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000539 AC: 771 AN: 1429338 Hom.: 1 Cov.: 30 AF XY: 0.000512 AC XY: 364 AN XY: 710348

Gnomad4 AFR exome AF: 0.0000640

Gnomad4 AMR exome AF: 0.0000291

Gnomad4 ASJ exome AF: 0.000124

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000303

Gnomad4 NFE exome AF: 0.000664

Gnomad4 OTH exome AF: 0.000289

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152226 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74370

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000676

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000787 Hom.: 0

Bravo AF: 0.000302

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000313 AC: 38

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

Dec 28, 2023

The c.423A>C (p.K141N) alteration is located in exon 4 (coding exon 3) of the PYHIN1 gene. This alteration results from a A to C substitution at nucleotide position 423, causing the lysine (K) at amino acid position 141 to be replaced by an asparagine (N). 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	-0.64	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.0070
Dann	Benign	0.13
DEOGEN2	Benign	0.0045	T;T;.;.;.;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00084	N
LIST_S2	Benign	0.46	T;T;T;T;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.022	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.51	N;N;N;N;N;N
REVEL	Benign	0.031
Sift	Benign	0.24	T;T;T;T;T;T
Sift4G	Benign	0.48	T;T;T;T;T;T
Polyphen		0.0, 0.0010, 0.018	.;B;B;B;B;B
Vest4		0.090, 0.094, 0.11, 0.10, 0.12
MutPred		0.20		Loss of methylation at K141 (P = 0.0042);Loss of methylation at K141 (P = 0.0042);.;Loss of methylation at K141 (P = 0.0042);.;Loss of methylation at K141 (P = 0.0042);
MVP		0.040
MPC		0.092
ClinPred		0.057	T
GERP RS		-4.2
Varity_R		0.038
gMVP		0.047

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: rs144650936; hg19: chr1-158908881;