5-129095062-C-A

Variant names:

• chr5-129095062-C-A
• rs1346218852
• NM_016048.2:c.296C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_016048.2(ISOC1):​c.296C>A​(p.Pro99Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000701 in 1,426,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P99L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71
• 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]

LOC124901060 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.797

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.296C>A	p.Pro99Gln	missense	Exon 1 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.296C>A	p.Pro99Gln	missense	Exon 1 of 5	ENSP00000173527.5	Q96CN7
	ISOC1	ENST00000868049.1		c.296C>A	p.Pro99Gln	missense	Exon 1 of 5	ENSP00000538108.1
	ISOC1	ENST00000868048.1		c.296C>A	p.Pro99Gln	missense	Exon 1 of 4	ENSP00000538107.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1426516 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 707682

African (AFR) AF: 0.00 AC: 0 AN: 32208

American (AMR) AF: 0.00 AC: 0 AN: 42236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25218

East Asian (EAS) AF: 0.00 AC: 0 AN: 37894

South Asian (SAS) AF: 0.00 AC: 0 AN: 83038

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5140

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097788

Other (OTH) AF: 0.00 AC: 0 AN: 59140

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.023	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.052	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.23	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.97	D
Vest4		0.67
MutPred		0.42		Gain of MoRF binding (P = 0.0982)
MVP		0.57
MPC		0.47
ClinPred		0.93	D
GERP RS		3.4
PromoterAI		-0.074	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.41
gMVP		0.54
Mutation Taster		=56/44	polymorphism

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: rs1346218852; hg19: chr5-128430755; COSMIC: COSV51491977; COSMIC: COSV51491977;