Variant 14-104753244-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006427.4(SIVA1):c.43C>A(p.Gln15Lys) variant causes a missense change involving the alteration of a non-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: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SIVA1
NM_006427.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.13

Variant links:

Genes affected

SIVA1 (HGNC:17712): (SIVA1 apoptosis inducing factor) This gene encodes an E3 ubiquitin ligase that regulates cell cycle progression, cell proliferation and apoptosis. The N-terminus of this protein binds to the cytoplasmic tail of the CD27 antigen, a member of the tumor necrosis factor receptor (TNFR) superfamily. In response to UV radiation-induced DNA damage, this protein has been shown to mediate the ubiquitination of proliferating cell nuclear antigen (PCNA), an important step in translesion DNA synthesis. [provided by RefSeq, Sep 2018]

SIVA1 links:

SIVA1 (HGNC:):

SIVA1 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.941

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIVA1	NM_006427.4 linkuse as main transcript	c.43C>A	p.Gln15Lys	missense_variant	1/4	ENST00000329967.11	NP_006418.2	O15304-1
SIVA1	NM_021709.3 linkuse as main transcript	c.43C>A	p.Gln15Lys	missense_variant	1/3		NP_068355.1	O15304-2
SIVA1	XM_011536360.3 linkuse as main transcript	c.43C>A	p.Gln15Lys	missense_variant	1/4		XP_011534662.1
LOC107987209	XR_001750915.3 linkuse as main transcript	n.1122+3162G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIVA1	ENST00000329967.11 linkuse as main transcript	c.43C>A	p.Gln15Lys	missense_variant	1/4	1	NM_006427.4	ENSP00000329213.6		O15304-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1441714

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715892

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2023

The c.43C>A (p.Q15K) alteration is located in exon 1 (coding exon 1) of the SIVA1 gene. This alteration results from a C to A substitution at nucleotide position 43, causing the glutamine (Q) at amino acid position 15 to be replaced by a lysine (K). 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

0.77

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.;T

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.80

T;T;T;T

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.6

M;.;M;.

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.4

D;.;D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0060

D;.;D;D

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.79

MutPred

0.79

Gain of MoRF binding (P = 0.0326);Gain of MoRF binding (P = 0.0326);Gain of MoRF binding (P = 0.0326);Gain of MoRF binding (P = 0.0326);

MVP

0.59

MPC

1.1

ClinPred

0.99

GERP RS

5.5

Varity_R

0.78

gMVP

0.75

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over