14-104756712-C-G

Position:

• chr14-104756712-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006427.4(SIVA1):​c.422C>G​(p.Thr141Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,614,056 control chromosomes in the GnomAD database, including 46 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0094 (18 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (28 hom.)
• Consequence: SIVA1 NM_006427.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.188

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]

LOC107987209 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047448575).
• BP6: Variant 14-104756712-C-G is Benign according to our data. Variant chr14-104756712-C-G is described in ClinVar as [Benign]. Clinvar id is 729186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00943 (1437/152340) while in subpopulation AFR AF= 0.0334 (1390/41572). AF 95% confidence interval is 0.032. There are 18 homozygotes in gnomad4. There are 622 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 18 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIVA1	NM_006427.4	c.422C>G	p.Thr141Ser	missense_variant	3/4	ENST00000329967.11
LOC107987209	XR_001750915.3	n.816G>C		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIVA1	ENST00000329967.11	c.422C>G	p.Thr141Ser	missense_variant	3/4	1	NM_006427.4	P1

Frequencies

GnomAD3 genomes AF: 0.00945 AC: 1439 AN: 152222 Hom.: 18 Cov.: 33

Gnomad AFR AF: 0.0336

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00238 AC: 596 AN: 250314 Hom.: 7 AF XY: 0.00171 AC XY: 231 AN XY: 135268

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000798

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.00101 AC: 1481 AN: 1461716 Hom.: 28 Cov.: 31 AF XY: 0.000872 AC XY: 634 AN XY: 727178

Gnomad4 AFR exome AF: 0.0385

Gnomad4 AMR exome AF: 0.00110

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00943 AC: 1437 AN: 152340 Hom.: 18 Cov.: 33 AF XY: 0.00835 AC XY: 622 AN XY: 74502

Gnomad4 AFR AF: 0.0334

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00317 Hom.: 3

Bravo AF: 0.0106

ESP6500AA AF: 0.0334 AC: 147

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00311 AC: 377

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	12
DANN	Benign	0.86
DEOGEN2	Benign	0.070	T;.;.;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.44	T;T;T;T;T
MetaRNN	Benign	0.0047	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.36	N;.;N;N;.
REVEL	Benign	0.019
Sift	Benign	0.29	T;.;T;T;.
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.065	B;B;B;.;.
Vest4		0.13
MutPred		0.57		Gain of catalytic residue at G144 (P = 0);Gain of catalytic residue at G144 (P = 0);.;Gain of catalytic residue at G144 (P = 0);.;
MVP		0.19
MPC		0.26
ClinPred		0.0022	T
GERP RS		0.36
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.024
gMVP		0.078

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

LitVar

Other links and lift over

dbSNP: rs8010264; hg19: chr14-105223049; COSMIC: COSV100328633;