20-13270741-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_080826.2(ISM1):c.376C>G(p.Gln126Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000487 in 1,613,250 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00074 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (8 hom.)
• Consequence: ISM1 NM_080826.2 missense, splice_region
• Scores: Splicing: ADA: 0.9059
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.14

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010455579).
• BP6: Variant 20-13270741-C-G is Benign according to our data. Variant chr20-13270741-C-G is described in ClinVar as [Benign]. Clinvar id is 3044524.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000742 (113/152312) while in subpopulation EAS AF= 0.0195 (101/5186). AF 95% confidence interval is 0.0164. There are 3 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ISM1	NM_080826.2	c.376C>G	p.Gln126Glu	missense_variant, splice_region_variant	2/6	ENST00000262487.5
ISM1	XM_017027680.2	c.376C>G	p.Gln126Glu	missense_variant, splice_region_variant	2/7
TASP1	XR_001754319.3	n.1369+45229G>C		intron_variant, non_coding_transcript_variant
TASP1	XR_007067463.1	n.1370-4559G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ISM1	ENST00000262487.5	c.376C>G	p.Gln126Glu	missense_variant, splice_region_variant	2/6	5	NM_080826.2	P1

Frequencies

GnomAD3 genomes AF: 0.000756 AC: 115 AN: 152194 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0196

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00155 AC: 383 AN: 247850 Hom.: 3 AF XY: 0.00141 AC XY: 190 AN XY: 134430

Gnomad AFR exome AF: 0.0000650

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0210

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.000460 AC: 672 AN: 1460938 Hom.: 8 Cov.: 32 AF XY: 0.000494 AC XY: 359 AN XY: 726644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0156

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000900

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152312 Hom.: 3 Cov.: 33 AF XY: 0.000806 AC XY: 60 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000687 Hom.: 1

Bravo AF: 0.000986

ExAC AF: 0.00147 AC: 178

Asia WGS AF: 0.00577 AC: 20 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ISM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 07, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.19
Sift	Benign	0.084	T
Sift4G	Benign	0.11	T
Polyphen		0.98	D
Vest4		0.85
MVP		0.63
MPC		0.042
ClinPred		0.068	T
GERP RS		5.7
Varity_R		0.34
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.91
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.070		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: rs75146235; hg19: chr20-13251388; COSMIC: COSV52606285;