Genetic Variant ISOC1:p.Leu9Pro (chr5-129094792-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_016048.2(ISOC1):c.26T>C(p.Leu9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000073 in 1,370,584 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 Likely benign (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

ISOC1
NM_016048.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.276

Publications

0 publications found

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: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.055354536).

BP6

Variant 5-129094792-T-C is Benign according to our data. Variant chr5-129094792-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 2247284.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2 link	c.26T>C	p.Leu9Pro	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2	Q96CN7
LOC124901060	XR_007058926.1 link	n.839A>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.26T>C	p.Leu9Pro	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5		Q96CN7
ISOC1	ENST00000514194.5 link	c.26T>C	p.Leu9Pro	missense_variant	Exon 1 of 3	3		ENSP00000421273.1		D6RGE2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.30e-7

AC:

AN:

1370584

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676012

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29646

American (AMR)

AF:

0.00

AC:

AN:

34054

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24694

East Asian (EAS)

AF:

0.00

AC:

AN:

33808

South Asian (SAS)

AF:

0.00

AC:

AN:

77258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4192

European-Non Finnish (NFE)

AF:

9.32e-7

AC:

AN:

1072482

Other (OTH)

AF:

0.00

AC:

AN:

57132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Aug 30, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.044

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0074

T;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.36

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.34

.;N

PhyloP100

0.28

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.090

N;N

REVEL

Benign

0.024

Sift

Benign

0.43

T;T

Sift4G

Benign

0.13

T;T

Polyphen

0.0

.;B

Vest4

0.15

MutPred

0.27

Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);

MVP

0.22

MPC

0.44

ClinPred

0.081

GERP RS

0.83

PromoterAI

-0.049

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.076

gMVP

0.38

Mutation Taster

=97/3

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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5-129094792-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over