1-158938501-C-A

Variant names:

• chr1-158938501-C-A
• rs563757453
• NM_152501.5:c.370C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152501.5(PYHIN1):​c.370C>A​(p.Arg124Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 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. R124G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0260
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038422585).

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.370C>A	p.Arg124Ser	missense	Exon 3 of 9	NP_689714.2
	PYHIN1	NM_198928.5		c.343C>A	p.Arg115Ser	missense	Exon 3 of 9	NP_945146.1	Q6K0P9-2
	PYHIN1	NM_198929.5		c.370C>A	p.Arg124Ser	missense	Exon 3 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.370C>A	p.Arg124Ser	missense	Exon 3 of 9	ENSP00000357122.1	Q6K0P9-1
	PYHIN1	ENST00000368138.7	TSL:1	c.343C>A	p.Arg115Ser	missense	Exon 3 of 9	ENSP00000357120.3	Q6K0P9-2
	PYHIN1	ENST00000392254.6	TSL:1	c.370C>A	p.Arg124Ser	missense	Exon 3 of 8	ENSP00000376083.2	Q6K0P9-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.2
DANN	Benign	0.42
DEOGEN2	Benign	0.0027	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00056	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.026
PrimateAI	Benign	0.19	T
PROVEAN	Benign	0.94	N
REVEL	Benign	0.018
Sift	Benign	0.15	T
Sift4G	Benign	0.49	T
Polyphen		0.019	B
Vest4		0.10
MutPred		0.28		Loss of methylation at R124 (P = 0.027)
MVP		0.048
MPC		0.090
ClinPred		0.044	T
GERP RS		-4.6
Varity_R		0.090
gMVP		0.084
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs563757453; hg19: chr1-158908291;