chr2-127498236-C-A

Variant names:

• chr2-127498236-C-A
• NM_017969.3:c.1469G>T

Variant summary

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

The NM_017969.3(IWS1):​c.1469G>T​(p.Gly490Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: IWS1 NM_017969.3 missense, splice_region
• Scores: Splicing: ADA: 0.1838
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.67

Genes affected

IWS1 (HGNC:25467): (interacts with SUPT6H, CTD assembly factor 1) Involved in regulation of histone modification; regulation of mRNA export from nucleus; and regulation of mRNA processing. Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000231731 (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 rank	MANE	Protein	UniProt
IWS1	NM_017969.3	c.1469G>T	p.Gly490Val	missense_variant, splice_region_variant	Exon 6 of 14	ENST00000295321.9	NP_060439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
IWS1	ENST00000295321.9	c.1469G>T	p.Gly490Val	missense_variant, splice_region_variant	Exon 6 of 14	1	NM_017969.3	ENSP00000295321.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1469G>T (p.G490V) alteration is located in exon 6 (coding exon 6) of the IWS1 gene. This alteration results from a G to T substitution at nucleotide position 1469, causing the glycine (G) at amino acid position 490 to be replaced by a valine (V). 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	0.99
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.57
MutPred		0.31		Gain of loop (P = 0.0195);
MVP		0.48
MPC		2.5
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.68
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.18
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.030		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: chr2-128255812;