Variant 1-158939091-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.44

Variant links:

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]

PYHIN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Protein	UniProt
PYHIN1	NM_152501.5 linkuse as main transcript	c.423A>C	p.Lys141Asn	missense_variant	4/9	ENST00000368140.6	NP_689714.2	Q6K0P9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYHIN1	ENST00000368140.6 linkuse as main transcript	c.423A>C	p.Lys141Asn	missense_variant	4/9	1	NM_152501.5	ENSP00000357122.1		Q6K0P9-1

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

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:

AN:

221564

Hom.:

AF XY:

0.000358

AC XY:

AN XY:

120134

show subpopulations

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.:

Cov.:

AF XY:

0.000512

AC XY:

364

AN XY:

710348

show subpopulations

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:

AN:

152226

Hom.:

Cov.:

AF XY:

0.000376

AC XY:

AN XY:

74370

show subpopulations

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.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

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

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

LIST_S2

Benign

0.46

T;T;T;T;T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.022

T;T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

.;N;.;N;.;N

PrimateAI

Benign

0.24

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over