14-77751457-A-C

Position:

• chr14-77751457-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_012245.3(SNW1):​c.192T>G​(p.Phe64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SNW1 NM_012245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.705

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]

SNW1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SNW1	NM_012245.3	c.192T>G	p.Phe64Leu	missense_variant	3/14	ENST00000261531.12	NP_036377.1
SNW1	NM_001318844.2	c.192T>G	p.Phe64Leu	missense_variant	3/13		NP_001305773.1
SNW1	XM_047431112.1	c.192T>G	p.Phe64Leu	missense_variant	3/12		XP_047287068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SNW1	ENST00000261531.12	c.192T>G	p.Phe64Leu	missense_variant	3/14	1	NM_012245.3	ENSP00000261531.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Feb 11, 2022

The c.192T>G (p.F64L) alteration is located in exon 3 (coding exon 3) of the SNW1 gene. This alteration results from a T to G substitution at nucleotide position 192, causing the phenylalanine (F) at amino acid position 64 to be replaced by a leucine (L). 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	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D;D;.
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.74	D;D;D
MetaSVM	Uncertain	-0.096	T
MutationAssessor	Pathogenic	3.1	M;.;.
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.0	D;D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		0.24	B;D;.
Vest4		0.97
MutPred		0.69		Gain of catalytic residue at E66 (P = 3e-04);Gain of catalytic residue at E66 (P = 3e-04);Gain of catalytic residue at E66 (P = 3e-04);
MVP		0.87
MPC		0.87
ClinPred		0.99	D
GERP RS		0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.83

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-78217800;