20-13279689-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080826.2(ISM1):​c.434C>T​(p.Pro145Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,613,958 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 (★).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

ISM1
NM_080826.2 missense

Scores

7
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.00
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.17929462).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ISM1NM_080826.2 linkc.434C>T p.Pro145Leu missense_variant Exon 3 of 6 ENST00000262487.5 NP_543016.1 B1AKI9
ISM1XM_017027680.2 linkc.434C>T p.Pro145Leu missense_variant Exon 3 of 7 XP_016883169.1
TASP1XR_001754319.3 linkn.1369+36281G>A intron_variant Intron 14 of 14
TASP1XR_007067463.1 linkn.1370-13507G>A intron_variant Intron 14 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ISM1ENST00000262487.5 linkc.434C>T p.Pro145Leu missense_variant Exon 3 of 6 5 NM_080826.2 ENSP00000262487.3 B1AKI9

Frequencies

GnomAD3 genomes
AF:
0.0000789
AC:
12
AN:
152146
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000145
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000281
AC:
7
AN:
248970
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135072
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000621
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000113
AC:
165
AN:
1461694
Hom.:
0
Cov.:
33
AF XY:
0.000107
AC XY:
78
AN XY:
727128
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000133
Gnomad4 OTH exome
AF:
0.000149
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152264
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74450
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000762
Hom.:
0
Bravo
AF:
0.0000756
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Oct 03, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.434C>T (p.P145L) alteration is located in exon 3 (coding exon 3) of the ISM1 gene. This alteration results from a C to T substitution at nucleotide position 434, causing the proline (P) at amino acid position 145 to be replaced by a leucine (L). 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
0.075
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.37
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.016
T
Eigen
Uncertain
0.39
Eigen_PC
Uncertain
0.52
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.89
D
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.18
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
PrimateAI
Benign
0.43
T
PROVEAN
Uncertain
-2.9
D
REVEL
Benign
0.11
Sift
Uncertain
0.011
D
Sift4G
Benign
0.075
T
Polyphen
0.92
P
Vest4
0.46
MVP
0.24
MPC
0.039
ClinPred
0.33
T
GERP RS
5.8
Varity_R
0.17
gMVP
0.33

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs748803763; hg19: chr20-13260336; COSMIC: COSV52603681; API