Genetic Variant NM_016048.2:c.53G>C (chr5-129094819-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016048.2(ISOC1):c.53G>C(p.Gly18Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000519 in 1,540,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

ISOC1
NM_016048.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

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:

LOC124901060 (HGNC:):

LOC124901060 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16156945).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2 link	c.53G>C	p.Gly18Ala	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2	Q96CN7
LOC124901060	XR_007058926.1 link	n.812C>G		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC1	ENST00000173527.6 link	c.53G>C	p.Gly18Ala	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5		Q96CN7
ISOC1	ENST00000514194.5 link	c.53G>C	p.Gly18Ala	missense_variant	Exon 1 of 3	3		ENSP00000421273.1		D6RGE2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152118

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:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000432

AC:

AN:

1388314

Hom.:

Cov.:

AF XY:

0.00000438

AC XY:

AN XY:

685208

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31088

American (AMR)

AF:

0.00

AC:

AN:

35280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24992

East Asian (EAS)

AF:

0.00

AC:

AN:

35640

South Asian (SAS)

AF:

0.00

AC:

AN:

78538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4602

European-Non Finnish (NFE)

AF:

0.00000463

AC:

AN:

1078900

Other (OTH)

AF:

0.0000173

AC:

AN:

57770

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74318

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 27, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.53G>C (p.G18A) alteration is located in exon 1 (coding exon 1) of the ISOC1 gene. This alteration results from a G to C substitution at nucleotide position 53, causing the glycine (G) at amino acid position 18 to be replaced by an alanine (A). 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

0.066

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.0051

T;T

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.59

T;T

M_CAP

Pathogenic

0.60

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

PhyloP100

1.6

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

0.050

N;N

REVEL

Benign

0.085

Sift

Benign

0.54

T;T

Sift4G

Benign

0.66

T;T

Polyphen

0.0

.;B

Vest4

0.22

MVP

0.17

MPC

0.82

ClinPred

0.23

GERP RS

2.0

PromoterAI

0.14

Neutral

(source)

Varity_R

0.090

gMVP

0.28

Mutation Taster

=100/0

polymorphism

(source)

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

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NM_016048.2:c.53G>C

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