12-108526316-G-A

Variant names:

• chr12-108526316-G-A
• NM_014706.4:c.2153C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP5

The NM_014706.4(SART3):​c.2153C>T​(p.Pro718Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: SART3 NM_014706.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• disseminated superficial actinic porokeratosis

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• complex neurodevelopmental disorder

  Inheritance: AR Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-108526316-G-A is Pathogenic according to our data. Variant chr12-108526316-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2444511.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014706.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SART3	NM_014706.4	MANE Select	c.2153C>T	p.Pro718Leu	missense	Exon 16 of 19	NP_055521.1	Q15020-1
	SART3	NM_001410983.1		c.2207C>T	p.Pro736Leu	missense	Exon 16 of 19	NP_001397912.1	A0A499FI31

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SART3	ENST00000546815.6	TSL:5 MANE Select	c.2153C>T	p.Pro718Leu	missense	Exon 16 of 19	ENSP00000449386.2	Q15020-1
	SART3	ENST00000228284.8	TSL:1	c.2207C>T	p.Pro736Leu	missense	Exon 16 of 19	ENSP00000228284.4	A0A499FI31
	SART3	ENST00000431469.6	TSL:1	c.2045C>T	p.Pro682Leu	missense	Exon 15 of 18	ENSP00000414453.2	Q15020-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Intellectual disability, Neurodevelopmental defects and Developmental delay with 46,XY gonadal dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.054	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	1.9	L
PhyloP100		9.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.38
Sift	Benign	0.14	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.46		Gain of catalytic residue at Y713 (P = 0.0169)
MVP		0.37
MPC		0.84
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		-0.0092	Neutral
Varity_R		0.19
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

hg19: chr12-108920093;