Genetic Variant NM_017969.3:c.1325A>G (chr2-127503471-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_017969.3(IWS1):c.1325A>G(p.Glu442Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

IWS1
NM_017969.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.45

Publications

0 publications found

Variant links:

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 links:

ENSG00000231731 (HGNC:):

ENSG00000231731 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11110821).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017969.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IWS1	NM_017969.3	MANE Select	c.1325A>G	p.Glu442Gly	missense	Exon 4 of 14	NP_060439.2	Q96ST2-1
	IWS1	NM_001410923.1		c.1325A>G	p.Glu442Gly	missense	Exon 4 of 15	NP_001397852.1	A0A1B0GW95

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
IWS1	ENST00000295321.9	TSL:1 MANE Select	c.1325A>G	p.Glu442Gly	missense	Exon 4 of 14	ENSP00000295321.4	Q96ST2-1
IWS1	ENST00000637187.2	TSL:5	c.1325A>G	p.Glu442Gly	missense	Exon 4 of 15	ENSP00000490836.2	A0A1B0GW95
IWS1	ENST00000866713.1		c.1322A>G	p.Glu441Gly	missense	Exon 4 of 14	ENSP00000536772.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000797

AC:

AN:

251008

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000581

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461168

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.0000447

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53288

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111638

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.023

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

5.5

PrimateAI

Benign

0.42

PROVEAN

Benign

-2.1

REVEL

Benign

0.056

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.054

Polyphen

0.22

Vest4

0.29

MutPred

0.21

Loss of helix (P = 0.079)

MVP

0.22

MPC

0.59

ClinPred

0.55

GERP RS

3.0

Varity_R

0.11

gMVP

0.026

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over