chr12-108523553-G-C

Variant names:

• chr12-108523553-G-C
• rs34709181
• NM_014706.4:c.2796C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014706.4(SART3):​c.2796C>G​(p.Asn932Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. N932N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SART3 NM_014706.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.71
• Publications: 0 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]

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]

FICD Gene-Disease associations (from GenCC):

• spastic paraplegia 92, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21929428).

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.2796C>G	p.Asn932Lys	missense	Exon 19 of 19	NP_055521.1	Q15020-1
	SART3	NM_001410983.1		c.2850C>G	p.Asn950Lys	missense	Exon 19 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.2796C>G	p.Asn932Lys	missense	Exon 19 of 19	ENSP00000449386.2	Q15020-1
	SART3	ENST00000228284.8	TSL:1	c.2850C>G	p.Asn950Lys	missense	Exon 19 of 19	ENSP00000228284.4	A0A499FI31
	SART3	ENST00000431469.6	TSL:1	c.2688C>G	p.Asn896Lys	missense	Exon 18 of 18	ENSP00000414453.2	Q15020-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727202

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

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5708

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111996

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	1.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.059	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		-1.7
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.036	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.40		Gain of methylation at N932 (P = 0.0081)
MVP		0.53
MPC		0.28
ClinPred		0.87	D
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
Mutation Taster		=49/51	disease causing

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

dbSNP: rs34709181; hg19: chr12-108917330;