14-77718509-C-A

Variant names:

• chr14-77718509-C-A
• NM_012245.3:c.1270G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012245.3(SNW1):​c.1270G>T​(p.Gly424Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,814 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SNW1 NM_012245.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.94

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30700558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SNW1	NM_012245.3	c.1270G>T	p.Gly424Cys	missense_variant	Exon 13 of 14	ENST00000261531.12	NP_036377.1
SNW1	NM_001318844.2	c.1270G>T	p.Gly424Cys	missense_variant	Exon 13 of 13		NP_001305773.1
SNW1	XM_047431112.1	c.1173G>T	p.Gln391His	missense_variant	Exon 12 of 12		XP_047287068.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SNW1	ENST00000261531.12	c.1270G>T	p.Gly424Cys	missense_variant	Exon 13 of 14	1	NM_012245.3	ENSP00000261531.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459814 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1270G>T (p.G424C) alteration is located in exon 13 (coding exon 13) of the SNW1 gene. This alteration results from a G to T substitution at nucleotide position 1270, causing the glycine (G) at amino acid position 424 to be replaced by a cysteine (C). 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	0.50
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	-0.089	T
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.55
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.49
MutPred		0.47		Gain of catalytic residue at I429 (P = 0.0032);.;Gain of catalytic residue at I429 (P = 0.0032);
MVP		0.59
MPC		1.1
ClinPred		0.95	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.54

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-78184852;