Genetic Variant SIVA1:p.Ala63Ala (chr14-104755700-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP7BA1

The NM_006427.4(SIVA1):c.189C>T(p.Ala63Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,613,528 control chromosomes in the GnomAD database, including 102,285 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.35 ( 9569 hom., cov: 33)

Exomes 𝑓: 0.35 ( 92716 hom. )

Consequence

SIVA1
NM_006427.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.253

Publications

45 publications found

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:

LOC107987209 (HGNC:):

LOC107987209 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.007).

BP7

Synonymous conserved (PhyloP=-0.253 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.593 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIVA1	NM_006427.4 link	c.189C>T	p.Ala63Ala	synonymous_variant	Exon 2 of 4	ENST00000329967.11	NP_006418.2	O15304-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIVA1	ENST00000329967.11 link	c.189C>T	p.Ala63Ala	synonymous_variant	Exon 2 of 4	1	NM_006427.4	ENSP00000329213.6		O15304-1

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52452

AN:

151968

Hom.:

9571

Cov.:

show subpopulations

Gnomad AFR

AF:

0.271

Gnomad AMI

AF:

0.299

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.305

Gnomad EAS

AF:

0.612

Gnomad SAS

AF:

0.507

Gnomad FIN

AF:

0.367

Gnomad MID

AF:

0.392

Gnomad NFE

AF:

0.335

Gnomad OTH

AF:

0.346

GnomAD2 exomes

AF:

0.394

AC:

99069

AN:

251212

AF XY:

0.391

show subpopulations

Gnomad AFR exome

AF:

0.266

Gnomad AMR exome

AF:

0.523

Gnomad ASJ exome

AF:

0.295

Gnomad EAS exome

AF:

0.609

Gnomad FIN exome

AF:

0.370

Gnomad NFE exome

AF:

0.334

Gnomad OTH exome

AF:

0.376

GnomAD4 exome

AF:

0.349

AC:

510120

AN:

1461440

Hom.:

92716

Cov.:

AF XY:

0.352

AC XY:

255677

AN XY:

727046

show subpopulations

African (AFR)

AF:

0.268

AC:

8980

AN:

33468

American (AMR)

AF:

0.510

AC:

22782

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.301

AC:

7876

AN:

26128

East Asian (EAS)

AF:

0.576

AC:

22869

AN:

39694

South Asian (SAS)

AF:

0.462

AC:

39807

AN:

86244

European-Finnish (FIN)

AF:

0.372

AC:

19851

AN:

53396

Middle Eastern (MID)

AF:

0.374

AC:

2128

AN:

5694

European-Non Finnish (NFE)

AF:

0.327

AC:

364060

AN:

1111760

Other (OTH)

AF:

0.361

AC:

21767

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

18545

37091

55636

74182

92727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11974

23948

35922

47896

59870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.345

AC:

52484

AN:

152088

Hom.:

9569

Cov.:

AF XY:

0.352

AC XY:

26166

AN XY:

74338

show subpopulations

African (AFR)

AF:

0.271

AC:

11267

AN:

41510

American (AMR)

AF:

0.447

AC:

6837

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.305

AC:

1057

AN:

3470

East Asian (EAS)

AF:

0.611

AC:

3148

AN:

5150

South Asian (SAS)

AF:

0.506

AC:

2438

AN:

4814

European-Finnish (FIN)

AF:

0.367

AC:

3880

AN:

10586

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.335

AC:

22736

AN:

67948

Other (OTH)

AF:

0.349

AC:

737

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1767

3534

5301

7068

8835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

518

1036

1554

2072

2590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.338

Hom.:

26829

Bravo

AF:

0.346

Asia WGS

AF:

0.536

AC:

1863

AN:

3478

EpiCase

AF:

0.348

EpiControl

AF:

0.331

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Benign

0.75

PhyloP100

-0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over