5-129105255-C-G

Variant names:

• chr5-129105255-C-G
• rs746472861
• NM_016048.2:c.500C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016048.2(ISOC1):​c.500C>G​(p.Thr167Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.05
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.957

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016048.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISOC1	NM_016048.2	MANE Select	c.500C>G	p.Thr167Arg	missense	Exon 3 of 5	NP_057132.2	Q96CN7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ISOC1	ENST00000173527.6	TSL:1 MANE Select	c.500C>G	p.Thr167Arg	missense	Exon 3 of 5	ENSP00000173527.5	Q96CN7
	ISOC1	ENST00000954509.1		c.455C>G	p.Thr152Arg	missense	Exon 3 of 5	ENSP00000624568.1
	ISOC1	ENST00000868049.1		c.440C>G	p.Thr147Arg	missense	Exon 3 of 5	ENSP00000538108.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.098	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		7.0
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.3	D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.86
MutPred		0.84		Loss of ubiquitination at K162 (P = 0.1191)
MVP		0.82
MPC		1.0
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.92
gMVP		0.85
Mutation Taster		=8/92	disease causing

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

Other links and lift over

dbSNP: rs746472861; hg19: chr5-128440948;