chr1-158937104-T-A

Variant names:

• chr1-158937104-T-A
• rs754795668
• NM_152501.5:c.194T>A

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.85
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152501.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYHIN1	NM_152501.5	MANE Select	c.194T>A	p.Leu65Gln	missense	Exon 2 of 9	NP_689714.2
	PYHIN1	NM_198928.5		c.194T>A	p.Leu65Gln	missense	Exon 2 of 9	NP_945146.1	Q6K0P9-2
	PYHIN1	NM_198929.5		c.194T>A	p.Leu65Gln	missense	Exon 2 of 8	NP_945147.1	Q6K0P9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYHIN1	ENST00000368140.6	TSL:1 MANE Select	c.194T>A	p.Leu65Gln	missense	Exon 2 of 9	ENSP00000357122.1	Q6K0P9-1
	PYHIN1	ENST00000368138.7	TSL:1	c.194T>A	p.Leu65Gln	missense	Exon 2 of 9	ENSP00000357120.3	Q6K0P9-2
	PYHIN1	ENST00000392254.6	TSL:1	c.194T>A	p.Leu65Gln	missense	Exon 2 of 8	ENSP00000376083.2	Q6K0P9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 250138 AF XY: 0.00

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460908 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726742

African (AFR) AF: 0.00 AC: 0 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111724

Other (OTH) AF: 0.00 AC: 0 AN: 60342

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.069	N
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.8
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.76		Gain of disorder (P = 0.0367)
MVP		0.53
MPC		0.46
ClinPred		0.80	D
GERP RS		2.8
Varity_R		0.58
gMVP		0.34
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs754795668; hg19: chr1-158906894;