13-45783940-C-A

Variant names:

• chr13-45783940-C-A
• NM_198849.3:c.253G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_198849.3(SIAH3):​c.253G>T​(p.Ala85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,451,606 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. A85V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SIAH3 NM_198849.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.489

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03856042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIAH3	NM_198849.3	c.253G>T	p.Ala85Ser	missense_variant	Exon 2 of 2	ENST00000400405.4	NP_942146.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIAH3	ENST00000400405.4	c.253G>T	p.Ala85Ser	missense_variant	Exon 2 of 2	1	NM_198849.3	ENSP00000383256.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1451606 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 721244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.253G>T (p.A85S) alteration is located in exon 2 (coding exon 2) of the SIAH3 gene. This alteration results from a G to T substitution at nucleotide position 253, causing the alanine (A) at amino acid position 85 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	Benign	0.074
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	2.3
DANN	Benign	0.61
DEOGEN2	Benign	0.011	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.039	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.34	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.038
Sift	Benign	0.12	T
Sift4G	Benign	0.62	T
Polyphen		0.0060	B
Vest4		0.095
MutPred		0.48		Gain of glycosylation at A85 (P = 0.0035);
MVP		0.014
MPC		0.14
ClinPred		0.047	T
GERP RS		0.45
Varity_R		0.081
gMVP		0.18

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: chr13-46358075;