Genetic Variant ISM1:p.Ala5Val (chr20-13221790-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_080826.2(ISM1):c.14C>T(p.Ala5Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000077 in 1,299,348 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 (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

ISM1
NM_080826.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 2.29

Publications

0 publications found

Variant links:

Genes affected

ISM1 (HGNC:16213): (isthmin 1) Predicted to be involved in negative regulation of angiogenesis. Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ISM1 links:

TASP1 (HGNC:15859): (taspase 1) This gene encodes an endopeptidase that cleaves specific substrates following aspartate residues. The encoded protein undergoes posttranslational autoproteolytic processing to generate alpha and beta subunits, which reassemble into the active alpha2-beta2 heterotetramer. It is required to cleave MLL, a protein required for the maintenance of HOX gene expression, and TFIIA, a basal transcription factor. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

TASP1 Gene-Disease associations (from GenCC):

Suleiman-El-Hattab syndrome
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia

TASP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.40946507).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080826.2. 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
	ISM1	NM_080826.2	MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 6	NP_543016.1	B1AKI9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISM1	ENST00000262487.5	TSL:5 MANE Select	c.14C>T	p.Ala5Val	missense	Exon 1 of 6	ENSP00000262487.3	B1AKI9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

71096

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

7.70e-7

AC:

AN:

1299348

Hom.:

Cov.:

AF XY:

0.00000156

AC XY:

AN XY:

640652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26304

American (AMR)

AF:

0.00

AC:

AN:

24176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22614

East Asian (EAS)

AF:

0.00

AC:

AN:

27622

South Asian (SAS)

AF:

0.00

AC:

AN:

69580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3908

European-Non Finnish (NFE)

AF:

9.62e-7

AC:

AN:

1039294

Other (OTH)

AF:

0.00

AC:

AN:

53560

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

ISM1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.016

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.85

MetaRNN

Benign

0.41

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.7

PhyloP100

2.3

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.21

REVEL

Benign

0.11

Sift

Benign

0.050

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.11

MutPred

0.35

Loss of methylation at E3 (P = 0.0567)

MVP

0.26

MPC

0.26

ClinPred

0.92

GERP RS

3.3

Varity_R

0.098

gMVP

0.82

Mutation Taster

=70/30

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over