12-108526257-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_014706.4(SART3):c.2212A>G(p.Ile738Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000765 in 1,614,092 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 (★).

Frequency

Genomes: 𝑓 0.00049 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00079 ( 0 hom. )

Consequence

SART3
NM_014706.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.42

Variant links:

Genes affected

SART3 (HGNC:16860): (spliceosome associated factor 3, U4/U6 recycling protein) The protein encoded by this gene is an RNA-binding nuclear protein that is a tumor-rejection antigen. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. This gene product is found to be an important cellular factor for HIV-1 gene expression and viral replication. It also associates transiently with U6 and U4/U6 snRNPs during the recycling phase of the spliceosome cycle. This encoded protein is thought to be involved in the regulation of mRNA splicing. [provided by RefSeq, Jul 2008]

SART3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.021131575).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000493 (75/152198) while in subpopulation NFE AF= 0.000838 (57/68032). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 28 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 75 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SART3	NM_014706.4 link	c.2212A>G	p.Ile738Val	missense_variant	Exon 16 of 19	ENST00000546815.6	NP_055521.1	Q15020-1
SART3	NM_001410983.1 link	c.2266A>G	p.Ile756Val	missense_variant	Exon 16 of 19		NP_001397912.1
SART3	XM_047429916.1 link	c.1348A>G	p.Ile450Val	missense_variant	Exon 11 of 14		XP_047285872.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SART3	ENST00000546815.6 link	c.2212A>G	p.Ile738Val	missense_variant	Exon 16 of 19	5	NM_014706.4	ENSP00000449386.2		Q15020-1

Frequencies

GnomAD3 genomes

AF:

0.000493

AC:

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.000838

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000461

AC:

116

AN:

251496

Hom.:

AF XY:

0.000456

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000932

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000793

AC:

1160

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000791

AC XY:

575

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000991

Gnomad4 OTH exome

AF:

0.000695

GnomAD4 genome

AF:

0.000493

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.000377

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000838

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000607

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000436

EpiControl

AF:

0.00119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2212A>G (p.I738V) alteration is located in exon 16 (coding exon 16) of the SART3 gene. This alteration results from a A to G substitution at nucleotide position 2212, causing the isoleucine (I) at amino acid position 738 to be replaced by a valine (V). 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

0.058

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.68

CADD

Benign

DANN

Benign

0.71

DEOGEN2

Benign

0.032

T;.;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.39

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.78

T;T;.

M_CAP

Benign

0.0058

MetaRNN

Benign

0.021

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.27

N;.;.

PrimateAI

Benign

0.42

PROVEAN

Benign

0.21

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.86

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0050

B;.;B

Vest4

0.15

MVP

0.082

MPC

0.19

ClinPred

0.0059

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.022

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over