3-150762770-G-A

Variant names:

• chr3-150762770-G-A
• rs755536279
• NM_005067.7:c.80C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005067.7(SIAH2):​c.80C>T​(p.Pro27Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000944 in 1,059,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P27R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 9.4e-7 (0 hom.)
• Consequence: SIAH2 NM_005067.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0260
• Publications: 2 publications found

Genes affected

SIAH2 (HGNC:10858): (siah E3 ubiquitin protein ligase 2) 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 regulating cellular response to hypoxia. [provided by RefSeq, Jul 2008]

SIAH2-AS1 (HGNC:40526): (SIAH2 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13982534).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005067.7. 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
	SIAH2	NM_005067.7	MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 1 of 2	NP_005058.3
	SIAH2-AS1	NR_187305.1		n.310+363G>A		intron	N/A
	SIAH2-AS1	NR_187306.1		n.113+363G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIAH2	ENST00000312960.4	TSL:1 MANE Select	c.80C>T	p.Pro27Leu	missense	Exon 1 of 2	ENSP00000322457.3	O43255
	SIAH2	ENST00000936558.1		c.80C>T	p.Pro27Leu	missense	Exon 1 of 3	ENSP00000606617.1
	SIAH2	ENST00000482706.1	TSL:3	c.-99-200C>T		intron	N/A	ENSP00000417619.1	C9J9D7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 9.44e-7 AC: 1 AN: 1059854 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 506828

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 21354

American (AMR) AF: 0.00 AC: 0 AN: 11882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11050

East Asian (EAS) AF: 0.00 AC: 0 AN: 21300

South Asian (SAS) AF: 0.00 AC: 0 AN: 22812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32936

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.00000112 AC: 1 AN: 896724

Other (OTH) AF: 0.00 AC: 0 AN: 39214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

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	0.093
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.54	T
M_CAP	Pathogenic	0.31	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.026
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.50	N
REVEL	Benign	0.10
Sift	Uncertain	0.022	D
Sift4G	Benign	0.14	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.27		Loss of glycosylation at P32 (P = 0.006)
MVP		0.34
MPC		0.98
ClinPred		0.23	T
GERP RS		0.24
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.093
gMVP		0.42
Mutation Taster		=90/10	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: rs755536279; hg19: chr3-150480557;