12-108523563-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_014706.4(SART3):c.2786A>G(p.Gln929Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000201 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: SART3 NM_014706.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

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]

FICD (HGNC:18416): (FIC domain protein adenylyltransferase) Enables several functions, including ATP binding activity; Hsp70 protein binding activity; and chaperone binding activity. Involved in protein adenylylation; regulation of IRE1-mediated unfolded protein response; and response to endoplasmic reticulum stress. Is integral component of endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12462652).
• BS2: High AC in GnomAd at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SART3	NM_014706.4	c.2786A>G	p.Gln929Arg	missense_variant	19/19	ENST00000546815.6
SART3	NM_001410983.1	c.2840A>G	p.Gln947Arg	missense_variant	19/19
SART3	XM_047429916.1	c.1922A>G	p.Gln641Arg	missense_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SART3	ENST00000546815.6	c.2786A>G	p.Gln929Arg	missense_variant	19/19	5	NM_014706.4	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000353

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000119 AC: 30 AN: 251318 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135864

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000289

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: 0.000246

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000205 AC: 300 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.000194 AC XY: 141 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000447

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: 0.000255

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74330

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000218

EpiControl AF: 0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.2786A>G (p.Q929R) alteration is located in exon 19 (coding exon 19) of the SART3 gene. This alteration results from a A to G substitution at nucleotide position 2786, causing the glutamine (Q) at amino acid position 929 to be replaced by an arginine (R). 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	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.043	T;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	0.93	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.079
Sift	Benign	0.23	T;T
Sift4G	Benign	0.24	T;T
Polyphen		0.32	B;.
Vest4		0.13
MVP		0.40
MPC		0.28
ClinPred		0.18	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs150379327; hg19: chr12-108917340;