12-108535360-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_014706.4(SART3):c.1555A>G(p.Arg519Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SART3 NM_014706.4 missense, splice_region
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.85

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-108535360-T-C is Pathogenic according to our data. Variant chr12-108535360-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2444512.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SART3	NM_014706.4	c.1555A>G	p.Arg519Gly	missense_variant, splice_region_variant	12/19	ENST00000546815.6
SART3	NM_001410983.1	c.1609A>G	p.Arg537Gly	missense_variant, splice_region_variant	12/19
SART3	XM_047429916.1	c.691A>G	p.Arg231Gly	missense_variant, splice_region_variant	7/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SART3	ENST00000546815.6	c.1555A>G	p.Arg519Gly	missense_variant, splice_region_variant	12/19	5	NM_014706.4	P1
	ENST00000662962.1	n.166-2156T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460946 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726824

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY gonadal dysgenesis Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Reproductive Development, Murdoch Childrens Research Institute

Mar 06, 2023

This variant was identified in an affected child in trans with a second variant in SART3 c.2153C>T (compound heterozygous). This variant was inherited from a heterozgyous unaffected mother. It was identified as part of a larger study that has found biallelic variants in SART3 in nine children from six families with overlapping clinical features. The variant falls in a highly conserved residue within an important HAT protein domain. The variant is extremely rare or absent in population databases. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	35
Dann	Uncertain	1.0
DEOGEN2	Benign	0.34	T;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D;D;.
M_CAP	Uncertain	0.095	D
MetaRNN	Uncertain	0.60	D;D;D
MetaSVM	Benign	-0.68	T
MutationAssessor	Pathogenic	3.2	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-6.0	D;D;D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.86
MutPred		0.48		Gain of catalytic residue at R519 (P = 0.0017);.;.;
MVP		0.77
MPC		0.94
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.90
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.58		Position offset: 38
DS_DL_spliceai		0.26		Position offset: -1

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-108929136;