NM_152501.5:c.506C>T

Variant names:

• chr1-158939174-C-T
• rs762187461
• NM_152501.5:c.506C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_152501.5(PYHIN1):​c.506C>T​(p.Thr169Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.94
• 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 -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040394545).
• BP6: Variant 1-158939174-C-T is Benign according to our data. Variant chr1-158939174-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2347396.Status of the report is criteria_provided_single_submitter, 1 stars.

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.506C>T	p.Thr169Met	missense	Exon 4 of 9	NP_689714.2
	PYHIN1	NM_198928.5		c.479C>T	p.Thr160Met	missense	Exon 4 of 9	NP_945146.1	Q6K0P9-2
	PYHIN1	NM_198929.5		c.506C>T	p.Thr169Met	missense	Exon 4 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.506C>T	p.Thr169Met	missense	Exon 4 of 9	ENSP00000357122.1	Q6K0P9-1
	PYHIN1	ENST00000368138.7	TSL:1	c.479C>T	p.Thr160Met	missense	Exon 4 of 9	ENSP00000357120.3	Q6K0P9-2
	PYHIN1	ENST00000392254.6	TSL:1	c.506C>T	p.Thr169Met	missense	Exon 4 of 8	ENSP00000376083.2	Q6K0P9-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251110 AF XY: 0.0000221

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: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461678 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727142

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.0000224 AC: 1 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86208

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111928

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.082
DANN	Benign	0.40
DEOGEN2	Benign	0.0067	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0022	N
LIST_S2	Benign	0.15	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.28	N
PhyloP100		-1.9
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.0050
Sift	Benign	0.43	T
Sift4G	Benign	0.34	T
Polyphen		0.0030	B
Vest4		0.10
MutPred		0.20		Loss of glycosylation at S168 (P = 0.0391)
MVP		0.040
MPC		0.081
ClinPred		0.017	T
GERP RS		-3.8
Varity_R		0.013
gMVP		0.13
Mutation Taster		=98/2	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: rs762187461; hg19: chr1-158908964; COSMIC: COSV63723147; COSMIC: COSV63723147;