Genetic Variant ISOC1:p.Arg148Gln (chr5-129105198-G-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016048.2(ISOC1):c.443G>A(p.Arg148Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ISOC1
NM_016048.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.09

Variant links:

Genes affected

ISOC1 (HGNC:24254): (isochorismatase domain containing 1) Predicted to be located in peroxisome. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ISOC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2 link	c.443G>A	p.Arg148Gln	missense_variant	Exon 3 of 5	ENST00000173527.6	NP_057132.2	Q96CN7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC1	ENST00000173527.6 link	c.443G>A	p.Arg148Gln	missense_variant	Exon 3 of 5	1	NM_016048.2	ENSP00000173527.5		Q96CN7
ISOC1	ENST00000514194.5 link	c.416G>A	p.Arg139Gln	missense_variant	Exon 3 of 3	3		ENSP00000421273.1		D6RGE2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151690

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000753

AC:

AN:

1461462

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33440

American (AMR)

AF:

0.00

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111804

Other (OTH)

AF:

0.0000166

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41388

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000194

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67888

Other (OTH)

AF:

0.00

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 18, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.443G>A (p.R148Q) alteration is located in exon 3 (coding exon 3) of the ISOC1 gene. This alteration results from a G to A substitution at nucleotide position 443, causing the arginine (R) at amino acid position 148 to be replaced by a glutamine (Q). 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

0.090

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.025

T;T

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.0064

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.080

.;N

PhyloP100

7.1

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.18

Sift

Benign

0.17

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.79

.;P

Vest4

0.74

MutPred

0.56

.;Loss of MoRF binding (P = 0.0764);

MVP

0.72

MPC

0.37

ClinPred

0.92

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.75

Mutation Taster

=58/42

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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5-129105198-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over