14-77718251-C-G

Variant names:

• chr14-77718251-C-G
• rs765182403
• NM_012245.3:c.1448G>C

Variant summary

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

The NM_012245.3(SNW1):​c.1448G>C​(p.Arg483Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SNW1 NM_012245.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

Genes affected

SNW1 (HGNC:16696): (SNW domain containing 1) This gene, a member of the SNW gene family, encodes a coactivator that enhances transcription from some Pol II promoters. This coactivator can bind to the ligand-binding domain of the vitamin D receptor and to retinoid receptors to enhance vitamin D-, retinoic acid-, estrogen-, and glucocorticoid-mediated gene expression. It can also function as a splicing factor by interacting with poly(A)-binding protein 2 to directly control the expression of muscle-specific genes at the transcriptional level. Finally, the protein may be involved in oncogenesis since it interacts with a region of SKI oncoproteins that is required for transforming activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

SLIRP (HGNC:20495): (SRA stem-loop interacting RNA binding protein) Steroid receptor RNA activator (SRA, or SRA1; MIM 603819) is a complex RNA molecule containing multiple stable stem-loop structures that functions in coactivation of nuclear receptors. SLIRP interacts with stem-loop structure-7 of SRA (STR7) and modulates nuclear receptor transactivation (Hatchell et al., 2006 [PubMed 16762838]).[supplied by OMIM, Mar 2008]

SLIRP Gene-Disease associations (from GenCC):

• inborn mitochondrial metabolism disorder

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia
• mitochondrial encephalomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: G2P

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=0.13423774).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012245.3. 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
	SNW1	NM_012245.3	MANE Select	c.1448G>C	p.Arg483Pro	missense	Exon 14 of 14	NP_036377.1	Q13573
	SNW1	NM_001318844.2		c.1528G>C	p.Val510Leu	missense	Exon 13 of 13	NP_001305773.1	G3V3A4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SNW1	ENST00000261531.12	TSL:1 MANE Select	c.1448G>C	p.Arg483Pro	missense	Exon 14 of 14	ENSP00000261531.8	Q13573
	SNW1	ENST00000555761.5	TSL:2	c.1528G>C	p.Val510Leu	missense	Exon 13 of 13	ENSP00000451129.1	G3V3A4
	SNW1	ENST00000851821.1		c.1475G>C	p.Arg492Pro	missense	Exon 14 of 14	ENSP00000521880.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.11
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		3.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.31
Sift	Benign	0.23	T
Sift4G	Benign	0.27	T
Polyphen		0.80	P
Vest4		0.35
MutPred		0.31		Gain of catalytic residue at R484 (P = 0.0064)
MVP		0.26
MPC		0.57
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.46
Mutation Taster		=70/30	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs765182403; hg19: chr14-78184594;