Genetic Variant NM_016048.2:c.71G>C (chr5-129094837-G-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016048.2(ISOC1):c.71G>C(p.Gly24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,556,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ISOC1
NM_016048.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.99

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.027362734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2 link	c.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2	Q96CN7
LOC124901060	XR_007058926.1 link	n.794C>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.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5		Q96CN7
ISOC1	ENST00000514194.5 link	c.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 3	3		ENSP00000421273.1		D6RGE2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000549

AC:

AN:

163966

AF XY:

0.0000227

show subpopulations

Gnomad AFR exome

AF:

0.000777

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000811

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000221

GnomAD4 exome

AF:

0.0000185

AC:

AN:

1404820

Hom.:

Cov.:

AF XY:

0.0000144

AC XY:

AN XY:

694116

show subpopulations

African (AFR)

AF:

0.000466

AC:

AN:

32212

American (AMR)

AF:

0.00

AC:

AN:

36372

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25176

East Asian (EAS)

AF:

0.0000539

AC:

AN:

37082

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79884

European-Finnish (FIN)

AF:

0.00

AC:

AN:

44450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5034

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086192

Other (OTH)

AF:

0.000137

AC:

AN:

58418

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000250

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.000893

AC:

AN:

41448

American (AMR)

AF:

0.0000654

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000227

ESP6500AA

AF:

0.000552

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000684

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.71G>C (p.G24A) 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 71, causing the glycine (G) at amino acid position 24 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

0.094

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

T;T

Eigen

Benign

-0.53

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.70

T;T

M_CAP

Pathogenic

0.58

MetaRNN

Benign

0.027

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

.;N

PhyloP100

3.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.0

N;N

REVEL

Benign

0.055

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.011

D;D

Polyphen

0.0010

.;B

Vest4

0.25

MVP

0.28

MPC

0.82

ClinPred

0.17

GERP RS

3.1

PromoterAI

0.097

Neutral

(source)

Varity_R

0.12

gMVP

0.26

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_016048.2:c.71G>C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over