14-77723221-G-C

Variant names:

• chr14-77723221-G-C
• NM_012245.3:c.1090C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012245.3(SNW1):​c.1090C>G​(p.Gln364Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SNW1 NM_012245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0
• 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):

• mitochondrial encephalomyopathy

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35714453).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNW1	NM_012245.3	c.1090C>G	p.Gln364Glu	missense_variant	Exon 11 of 14	ENST00000261531.12	NP_036377.1
SNW1	NM_001318844.2	c.1090C>G	p.Gln364Glu	missense_variant	Exon 11 of 13		NP_001305773.1
SNW1	XM_047431112.1	c.1034-2393C>G		intron_variant	Intron 10 of 11		XP_047287068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNW1	ENST00000261531.12	c.1090C>G	p.Gln364Glu	missense_variant	Exon 11 of 14	1	NM_012245.3	ENSP00000261531.8

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1090C>G (p.Q364E) alteration is located in exon 11 (coding exon 11) of the SNW1 gene. This alteration results from a C to G substitution at nucleotide position 1090, causing the glutamine (Q) at amino acid position 364 to be replaced by a glutamic acid (E). 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	22
DANN	Benign	0.88
DEOGEN2	Benign	0.21	T;T;T
Eigen	Benign	-0.099
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.36	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.46	N;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.44	N;N;N
REVEL	Benign	0.20
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.083	B;.;B
Vest4		0.65
MutPred		0.21		Gain of ubiquitination at K361 (P = 0.0506);.;Gain of ubiquitination at K361 (P = 0.0506);
MVP		0.64
MPC		1.4
ClinPred		0.48	T
GERP RS		5.6
Varity_R		0.18
gMVP		0.32
Mutation Taster		=20/80	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: chr14-78189564;