11-65966421-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005146.5(SART1):c.1053G>C(p.Leu351Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SART1 NM_005146.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.97

Genes affected

SART1 (HGNC:10538): (spliceosome associated factor 1, recruiter of U4/U6.U5 tri-snRNP) This gene encodes two proteins, the SART1(800) protein expressed in the nucleus of the majority of proliferating cells, and the SART1(259) protein expressed in the cytosol of epithelial cancers. The SART1(259) protein is translated by the mechanism of -1 frameshifting during posttranscriptional regulation; its full-length sequence is not published yet. The two encoded proteins are thought to be involved in the regulation of proliferation. Both proteins have tumor-rejection antigens. The SART1(259) protein possesses tumor epitopes capable of inducing HLA-A2402-restricted cytotoxic T lymphocytes in cancer patients. This SART1(259) antigen may be useful in specific immunotherapy for cancer patients and may serve as a paradigmatic tool for the diagnosis and treatment of patients with atopy. The SART1(259) protein is found to be essential for the recruitment of the tri-snRNP to the pre-spliceosome in the spliceosome assembly pathway. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SART1	NM_005146.5	c.1053G>C	p.Leu351Phe	missense_variant	9/20	ENST00000312397.10
SART1	XM_047427856.1	c.1053G>C	p.Leu351Phe	missense_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SART1	ENST00000312397.10	c.1053G>C	p.Leu351Phe	missense_variant	9/20	1	NM_005146.5	P1
SART1	ENST00000529532.5	n.1278G>C		non_coding_transcript_exon_variant	8/9	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

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

Dec 02, 2022

The c.1053G>C (p.L351F) alteration is located in exon 9 (coding exon 9) of the SART1 gene. This alteration results from a G to C substitution at nucleotide position 1053, causing the leucine (L) at amino acid position 351 to be replaced by a phenylalanine (F). 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	Pathogenic	0.75
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.77	T
MutationAssessor	Pathogenic	3.3	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.31
Sift	Benign	0.14	T
Sift4G	Benign	0.14	T
Polyphen		1.0	D
Vest4		0.64
MutPred		0.76		Loss of sheet (P = 0.0817);
MVP		0.65
MPC		1.0
ClinPred		0.94	D
GERP RS		0.11
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.8
Varity_R		0.052
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

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: chr11-65733892;