Genetic Variant ISOC1:p.Val89Leu (chr5-129095031-G-C) – 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.265G>C(p.Val89Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,998 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 (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

ISOC1
NM_016048.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.69

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 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.265G>C	p.Val89Leu	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2	Q96CN7
LOC124901060	XR_007058926.1 link	n.600C>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.265G>C	p.Val89Leu	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5		Q96CN7
ISOC1	ENST00000514194.5 link	c.265G>C	p.Val89Leu	missense_variant	Exon 1 of 3	3		ENSP00000421273.1		D6RGE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718494

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32702

American (AMR)

AF:

0.00

AC:

AN:

43170

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25856

East Asian (EAS)

AF:

0.00

AC:

AN:

38700

South Asian (SAS)

AF:

0.00

AC:

AN:

84562

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47782

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5546

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106792

Other (OTH)

AF:

0.00

AC:

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000285

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.265G>C (p.V89L) 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 265, causing the valine (V) at amino acid position 89 to be replaced by a leucine (L). 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

0.31

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0087

T;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.072

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.19

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-0.34

.;N

PhyloP100

2.7

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

0.17

N;N

REVEL

Benign

0.061

Sift

Benign

0.12

T;T

Sift4G

Benign

0.19

T;T

Polyphen

0.0030

.;B

Vest4

0.15

MutPred

0.26

Loss of methylation at K85 (P = 0.0794);Loss of methylation at K85 (P = 0.0794);

MVP

0.31

MPC

0.27

ClinPred

0.77

GERP RS

4.4

PromoterAI

-0.12

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Varity_R

0.17

gMVP

0.24

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: 17

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over