chr13-45783780-C-T

Variant names:

• chr13-45783780-C-T
• NM_198849.3:c.413G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198849.3(SIAH3):​c.413G>A​(p.Gly138Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIAH3 NM_198849.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.81
• Publications: 0 publications found

Genes affected

SIAH3 (HGNC:30553): (siah E3 ubiquitin protein ligase family member 3) Predicted to enable ubiquitin conjugating enzyme binding activity and ubiquitin protein ligase activity. Involved in negative regulation of protein targeting to mitochondrion and regulation of protein stability. Located in mitochondrion and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.937

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198849.3. 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
	SIAH3	NM_198849.3	MANE Select	c.413G>A	p.Gly138Glu	missense	Exon 2 of 2	NP_942146.2	Q8IW03

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIAH3	ENST00000400405.4	TSL:1 MANE Select	c.413G>A	p.Gly138Glu	missense	Exon 2 of 2	ENSP00000383256.2	Q8IW03

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.54	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		7.8
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.78		Gain of solvent accessibility (P = 0.0068)
MVP		0.27
MPC		0.77
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.87
gMVP		0.65
Mutation Taster		=48/52	disease causing

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

hg19: chr13-46357915;