20-13221790-C-T

Variant names:

• chr20-13221790-C-T
• rs1301553773
• NM_080826.2:c.14C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

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
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40946507).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISM1	NM_080826.2	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 6	ENST00000262487.5	NP_543016.1
ISM1	XM_017027680.2	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 7		XP_016883169.1
TASP1	XR_001754319.3	n.1369+94180G>A		intron_variant	Intron 14 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISM1	ENST00000262487.5	c.14C>T	p.Ala5Val	missense_variant	Exon 1 of 6	5	NM_080826.2	ENSP00000262487.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.70e-7 AC: 1 AN: 1299348 Hom.: 0 Cov.: 31 AF XY: 0.00000156 AC XY: 1 AN XY: 640652

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: 9.62e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

ISM1-related disorder Uncertain:1

Feb 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ISM1 c.14C>T variant is predicted to result in the amino acid substitution p.Ala5Val. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.85	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.11
Sift	Benign	0.050	D
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.11
MutPred		0.35		Loss of methylation at E3 (P = 0.0567);
MVP		0.26
MPC		0.26
ClinPred		0.92	D
GERP RS		3.3
Varity_R		0.098
gMVP		0.82

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: rs1301553773; hg19: chr20-13202437;