16-31216796-A-G

Position:

• chr16-31216796-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000302964.4(PYDC1):​c.233T>C​(p.Met78Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000633 in 1,610,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: PYDC1 ENST00000302964.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0460

Genes affected

PYDC1 (HGNC:30261): (pyrin domain containing 1) Predicted to enable cysteine-type endopeptidase activity. Involved in several processes, including negative regulation of tumor necrosis factor-mediated signaling pathway; regulation of gene expression; and tumor necrosis factor-mediated signaling pathway. Located in cytosol and nucleus. Part of IkappaB kinase complex. [provided by Alliance of Genome Resources, Apr 2022]

TRIM72 (HGNC:32671): (tripartite motif containing 72) Enables identical protein binding activity. Predicted to be involved in several processes, including cellular protein metabolic process; plasma membrane repair; and protein homooligomerization. Predicted to act upstream of or within negative regulation of insulin receptor signaling pathway; negative regulation of insulin-like growth factor receptor signaling pathway; and negative regulation of myotube differentiation. Predicted to be located in cytoplasmic vesicle membrane. Predicted to be active in cytoplasm and sarcolemma. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07617909).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYDC1	NM_152901.4	c.233T>C	p.Met78Thr	missense_variant	1/2	ENST00000302964.4	NP_690865.1
TRIM72	NM_001008274.4	c.390+1668A>G		intron_variant		ENST00000322122.8	NP_001008275.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYDC1	ENST00000302964.4	c.233T>C	p.Met78Thr	missense_variant	1/2	1	NM_152901.4	ENSP00000304336.4
TRIM72	ENST00000322122.8	c.390+1668A>G		intron_variant		2	NM_001008274.4	ENSP00000312675.3

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152194 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000723

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.000118

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000922 AC: 23 AN: 249560 Hom.: 0 AF XY: 0.0000961 AC XY: 13 AN XY: 135332

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000134

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.0000555 AC: 81 AN: 1458526 Hom.: 0 Cov.: 31 AF XY: 0.0000593 AC XY: 43 AN XY: 724992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000469

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152312 Hom.: 0 Cov.: 31 AF XY: 0.000161 AC XY: 12 AN XY: 74482

Gnomad4 AFR AF: 0.0000721

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000215

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

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

Dec 30, 2023

The c.233T>C (p.M78T) alteration is located in exon 1 (coding exon 1) of the PYDC1 gene. This alteration results from a T to C substitution at nucleotide position 233, causing the methionine (M) at amino acid position 78 to be replaced by a threonine (T). 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	0.59
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	10
DANN	Benign	0.38
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.072
Sift	Benign	0.048	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.67	P
Vest4		0.13
MVP		0.70
MPC		1.5
ClinPred		0.056	T
GERP RS		1.7
Varity_R		0.10
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs143371283; hg19: chr16-31228117;