1-158942074-T-C

Position:

• chr1-158942074-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_152501.5(PYHIN1):​c.677T>C​(p.Phe226Ser) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PYHIN1 NM_152501.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.96

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYHIN1	NM_152501.5	c.677T>C	p.Phe226Ser	missense_variant	5/9	ENST00000368140.6	NP_689714.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYHIN1	ENST00000368140.6	c.677T>C	p.Phe226Ser	missense_variant	5/9	1	NM_152501.5	ENSP00000357122.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 10, 2024

The c.677T>C (p.F226S) alteration is located in exon 5 (coding exon 4) of the PYHIN1 gene. This alteration results from a T to C substitution at nucleotide position 677, causing the phenylalanine (F) at amino acid position 226 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	-0.064
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.0	M;.;M;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-7.3	D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.71
MutPred		0.83		Gain of disorder (P = 0.0034);.;Gain of disorder (P = 0.0034);.;
MVP		0.76
MPC		0.59
ClinPred		0.92	D
GERP RS		2.9
Varity_R		0.59
gMVP		0.51

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-158911864;