5-129105016-G-A

Variant names:

• chr5-129105016-G-A
• rs376159501
• NM_016048.2:c.370G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016048.2(ISOC1):​c.370G>A​(p.Glu124Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,518 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. E124Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.93
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.867

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2	c.370G>A	p.Glu124Lys	missense_variant	Exon 2 of 5	ENST00000173527.6	NP_057132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC1	ENST00000173527.6	c.370G>A	p.Glu124Lys	missense_variant	Exon 2 of 5	1	NM_016048.2	ENSP00000173527.5
ISOC1	ENST00000514194.5	c.343G>A	p.Glu115Lys	missense_variant	Exon 2 of 3	3		ENSP00000421273.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461518 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111722

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T;T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.87	D;D
MetaSVM	Uncertain	0.15	D
MutationAssessor	Pathogenic	3.0	.;M
PhyloP100		8.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.5	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.95	.;P
Vest4		0.90
MutPred		0.69		.;Gain of MoRF binding (P = 0.0159);
MVP		0.65
MPC		1.0
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.70
gMVP		0.78
Mutation Taster		=29/71	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs376159501; hg19: chr5-128440709;