chr2-127502870-T-A

Variant names:

• chr2-127502870-T-A
• rs533950933
• NM_017969.3:c.1412A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_017969.3(IWS1):​c.1412A>T​(p.Asn471Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000132 in 1,519,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N471T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: IWS1 NM_017969.3 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.83
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.340845).

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.1412A>T	p.Asn471Ile	missense splice_region	Exon 5 of 14	NP_060439.2	Q96ST2-1
	IWS1	NM_001410923.1		c.1412A>T	p.Asn471Ile	missense splice_region	Exon 5 of 15	NP_001397852.1	A0A1B0GW95

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	IWS1	ENST00000295321.9	TSL:1 MANE Select	c.1412A>T	p.Asn471Ile	missense splice_region	Exon 5 of 14	ENSP00000295321.4	Q96ST2-1
	IWS1	ENST00000637187.2	TSL:5	c.1412A>T	p.Asn471Ile	missense splice_region	Exon 5 of 15	ENSP00000490836.2	A0A1B0GW95
	IWS1	ENST00000866713.1		c.1409A>T	p.Asn470Ile	missense splice_region	Exon 5 of 14	ENSP00000536772.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1366672 Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0 AN XY: 685078

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31538

American (AMR) AF: 0.00 AC: 0 AN: 43922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25408

East Asian (EAS) AF: 0.00 AC: 0 AN: 39136

South Asian (SAS) AF: 0.00 AC: 0 AN: 83220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5558

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1029530

Other (OTH) AF: 0.0000175 AC: 1 AN: 57188

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74506

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Benign	-0.36
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.099	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.8
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.13
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.59
MutPred		0.31		Loss of helix (P = 0.0093)
MVP		0.30
MPC		0.38
ClinPred		0.93	D
GERP RS		4.6
Varity_R		0.42
gMVP		0.029
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs533950933; hg19: chr2-128260446;