16-48362279-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_003031.4(SIAH1):c.150G>A(p.Pro50=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0029 in 1,614,108 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.013 (43 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (46 hom.)
• Consequence: SIAH1 NM_003031.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.347

Genes affected

SIAH1 (HGNC:10857): (siah E3 ubiquitin protein ligase 1) This gene encodes a protein that is a member of the seven in absentia homolog (SIAH) family. The protein is an E3 ligase and is involved in ubiquitination and proteasome-mediated degradation of specific proteins. The activity of this ubiquitin ligase has been implicated in the development of certain forms of Parkinson's disease, the regulation of the cellular response to hypoxia and induction of apoptosis. Alternative splicing results in several additional transcript variants, some encoding different isoforms and others that have not been fully characterized. [provided by RefSeq, Jul 2008]

LONP2 (HGNC:20598): (lon peptidase 2, peroxisomal) In human, peroxisomes function primarily to catalyze fatty acid beta-oxidation and, as a by-product, produce hydrogen peroxide and superoxide. The protein encoded by this gene is an ATP-dependent protease that likely plays a role in maintaining overall peroxisome homeostasis as well as proteolytically degrading peroxisomal proteins damaged by oxidation. The protein has an N-terminal Lon N substrate recognition domain, an ATPase domain, a proteolytic domain, and, in some isoforms, a C-terminal peroxisome targeting sequence. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 16-48362279-C-T is Benign according to our data. Variant chr16-48362279-C-T is described in ClinVar as [Benign]. Clinvar id is 779016.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2029/152216) while in subpopulation AFR AF= 0.0425 (1764/41516). AF 95% confidence interval is 0.0408. There are 43 homozygotes in gnomad4. There are 996 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 2006 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIAH1	NM_003031.4	c.150G>A	p.Pro50=	synonymous_variant	2/2	ENST00000394725.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIAH1	ENST00000394725.3	c.150G>A	p.Pro50=	synonymous_variant	2/2	1	NM_003031.4	P4

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2006 AN: 152098 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000944

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00548 AC: 1378 AN: 251482 Hom.: 23 AF XY: 0.00459 AC XY: 624 AN XY: 135918

Gnomad AFR exome AF: 0.0433

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.000694

Gnomad EAS exome AF: 0.0282

Gnomad SAS exome AF: 0.000751

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00182 AC: 2659 AN: 1461892 Hom.: 46 Cov.: 32 AF XY: 0.00163 AC XY: 1182 AN XY: 727248

Gnomad4 AFR exome AF: 0.0416

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.000344

Gnomad4 EAS exome AF: 0.0175

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000791

Gnomad4 OTH exome AF: 0.00439

GnomAD4 genome AF: 0.0133 AC: 2029 AN: 152216 Hom.: 43 Cov.: 32 AF XY: 0.0134 AC XY: 996 AN XY: 74400

Gnomad4 AFR AF: 0.0425

Gnomad4 AMR AF: 0.00464

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.0289

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.0000944

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00587 Hom.: 6

Bravo AF: 0.0149

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 30, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	12
Dann	Benign	0.84
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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

LitVar

Other links and lift over

dbSNP: rs34437640; hg19: chr16-48396190;