dbSNP rs754795668: PYHIN1:p.Leu65Gln (chr1-158937104-T-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_152501.5(PYHIN1):c.194T>A(p.Leu65Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,908 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L65R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PYHIN1
NM_152501.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.85

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYHIN1	NM_152501.5 link	c.194T>A	p.Leu65Gln	missense_variant	Exon 2 of 9	ENST00000368140.6	NP_689714.2	Q6K0P9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYHIN1	ENST00000368140.6 link	c.194T>A	p.Leu65Gln	missense_variant	Exon 2 of 9	1	NM_152501.5	ENSP00000357122.1		Q6K0P9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000400

AC:

AN:

250138

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135238

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460908

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000349

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Uncertain

0.031

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;T;.;.;.;.

Eigen

Benign

-0.041

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.069

LIST_S2

Uncertain

0.91

D;D;D;D;D;D

M_CAP

Benign

0.022

MetaRNN

Uncertain

0.68

D;D;D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.6

.;M;M;M;M;M

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-5.9

D;D;D;D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;D

Polyphen

1.0, 1.0

.;D;D;D;D;D

Vest4

0.82, 0.82, 0.82, 0.83

MutPred

0.76

Gain of disorder (P = 0.0367);Gain of disorder (P = 0.0367);Gain of disorder (P = 0.0367);Gain of disorder (P = 0.0367);Gain of disorder (P = 0.0367);Gain of disorder (P = 0.0367);

MVP

0.53

MPC

0.46

ClinPred

0.80

GERP RS

2.8

Varity_R

0.58

gMVP

0.34

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over