20-13221798-C-G

Variant summary

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

The NM_080826.2(ISM1):c.22C>G(p.Leu8Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ISM1 NM_080826.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.760

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:):

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=0.26605657).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISM1	NM_080826.2	c.22C>G	p.Leu8Val	missense_variant	1/6	ENST00000262487.5
ISM1	XM_017027680.2	c.22C>G	p.Leu8Val	missense_variant	1/7
TASP1	XR_001754319.3	n.1369+94172G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISM1	ENST00000262487.5	c.22C>G	p.Leu8Val	missense_variant	1/6	5	NM_080826.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.22C>G (p.L8V) alteration is located in exon 1 (coding exon 1) of the ISM1 gene. This alteration results from a C to G substitution at nucleotide position 22, causing the leucine (L) at amino acid position 8 to be replaced by a valine (V). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.22
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.80	D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.10
Sift	Uncertain	0.015	D
Sift4G	Benign	0.091	T
Polyphen		0.98	D
Vest4		0.27
MutPred		0.29		Loss of methylation at R3 (P = 0.1243);
MVP		0.58
MPC		0.26
ClinPred		0.93	D
GERP RS		3.3
Varity_R		0.097
gMVP		0.67

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: rs2039452293; hg19: chr20-13202445;