2-127489841-C-T

Position:

• chr2-127489841-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_017969.3(IWS1):​c.2150G>A​(p.Arg717Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000557 in 1,435,786 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: IWS1 NM_017969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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]

IWS1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1706444).
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
IWS1	NM_017969.3	c.2150G>A	p.Arg717Lys	missense_variant	11/14	ENST00000295321.9	NP_060439.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
IWS1	ENST00000295321.9	c.2150G>A	p.Arg717Lys	missense_variant	11/14	1	NM_017969.3	ENSP00000295321.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000557 AC: 8 AN: 1435786 Hom.: 0 Cov.: 27 AF XY: 0.00000559 AC XY: 4 AN XY: 716162

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: 0.00000643

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

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

Dec 03, 2024

The c.2150G>A (p.R717K) alteration is located in exon 11 (coding exon 11) of the IWS1 gene. This alteration results from a G to A substitution at nucleotide position 2150, causing the arginine (R) at amino acid position 717 to be replaced by a lysine (K). 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	Benign	0.21
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	23
DANN	Benign	0.96
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.053
Sift	Benign	0.18	T;.
Sift4G	Benign	0.24	T;.
Polyphen		0.025	B;.
Vest4		0.12
MVP		0.54
MPC		1.6
ClinPred		0.67	D
GERP RS		4.1
Varity_R		0.21
gMVP		0.78

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

LitVar

Other links and lift over

dbSNP: rs1469391150; hg19: chr2-128247417;