1-158942029-G-A

Variant names:

• chr1-158942029-G-A
• rs140327432
• NM_152501.5:c.632G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_152501.5(PYHIN1):​c.632G>A​(p.Arg211Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,612,496 control chromosomes in the GnomAD database, including 3 homozygotes. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00033 (3 hom.)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.44
• Publications: 4 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013454795).
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.632G>A	p.Arg211Gln	missense	Exon 5 of 9	NP_689714.2
	PYHIN1	NM_198928.5		c.605G>A	p.Arg202Gln	missense	Exon 5 of 9	NP_945146.1	Q6K0P9-2
	PYHIN1	NM_198929.5		c.632G>A	p.Arg211Gln	missense	Exon 5 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.632G>A	p.Arg211Gln	missense	Exon 5 of 9	ENSP00000357122.1	Q6K0P9-1
	PYHIN1	ENST00000368138.7	TSL:1	c.605G>A	p.Arg202Gln	missense	Exon 5 of 9	ENSP00000357120.3	Q6K0P9-2
	PYHIN1	ENST00000392254.6	TSL:1	c.632G>A	p.Arg211Gln	missense	Exon 5 of 8	ENSP00000376083.2	Q6K0P9-3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152118 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000436 AC: 109 AN: 250018 AF XY: 0.000451

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000408

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.0000545

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000325 AC: 475 AN: 1460260 Hom.: 3 Cov.: 31 AF XY: 0.000332 AC XY: 241 AN XY: 726320

African (AFR) AF: 0.000270 AC: 9 AN: 33352

American (AMR) AF: 0.000382 AC: 17 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00127 AC: 33 AN: 26058

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.000174 AC: 15 AN: 85984

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53374

Middle Eastern (MID) AF: 0.0128 AC: 74 AN: 5768

European-Non Finnish (NFE) AF: 0.000257 AC: 286 AN: 1111234

Other (OTH) AF: 0.000630 AC: 38 AN: 60314

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152236 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74440

African (AFR) AF: 0.0000722 AC: 3 AN: 41540

American (AMR) AF: 0.000589 AC: 9 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 68020

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000503 Hom.: 2

Bravo AF: 0.000295

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.000387 AC: 47

EpiCase AF: 0.000982

EpiControl AF: 0.000830

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.081
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.0080
DANN	Benign	0.32
DEOGEN2	Benign	0.0012	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.2	N
PhyloP100		-1.4
PrimateAI	Benign	0.19	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.023
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.012	B
Vest4		0.055
MVP		0.055
MPC		0.090
ClinPred		0.017	T
GERP RS		-5.7
Varity_R		0.017
gMVP		0.029
Mutation Taster		=100/0	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: rs140327432; hg19: chr1-158911819; COSMIC: COSV100932442; COSMIC: COSV100932442;