chr5-129094856-C-A

Variant names:

• chr5-129094856-C-A
• rs1753472694
• NM_016048.2:c.90C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016048.2(ISOC1):​c.90C>A​(p.Phe30Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,428,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.35
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3313082).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2	c.90C>A	p.Phe30Leu	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2
LOC124901060	XR_007058926.1	n.775G>T		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	c.90C>A	p.Phe30Leu	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5
ISOC1	ENST00000514194.5	c.90C>A	p.Phe30Leu	missense_variant	Exon 1 of 3	3		ENSP00000421273.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1428092 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 707286

⚠️ 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: 33112

American (AMR) AF: 0.00 AC: 0 AN: 39062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25414

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38510

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47822

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097430

Other (OTH) AF: 0.00 AC: 0 AN: 59334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.044843), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.012	T;T
Eigen	Benign	0.039
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.56	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	.;N
PhyloP100		5.4
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-0.13	N;N
REVEL	Benign	0.25
Sift	Benign	0.13	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.81	.;P
Vest4		0.29
MutPred		0.34		Gain of glycosylation at T25 (P = 0.1794);Gain of glycosylation at T25 (P = 0.1794);
MVP		0.33
MPC		0.32
ClinPred		0.69	D
GERP RS		3.2
PromoterAI		0.034	Neutral
Varity_R		0.22
gMVP		0.35
Mutation Taster		=69/31	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: rs1753472694; hg19: chr5-128430549;