chr5-129095034-A-G

Variant names:

• chr5-129095034-A-G
• rs1371332498
• NM_016048.2:c.268A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016048.2(ISOC1):​c.268A>G​(p.Ser90Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,596,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15884441).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2	c.268A>G	p.Ser90Gly	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2
LOC124901060	XR_007058926.1	n.597T>C		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.268A>G	p.Ser90Gly	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5
ISOC1	ENST00000514194.5	c.268A>G	p.Ser90Gly	missense_variant	Exon 1 of 3	3		ENSP00000421273.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 230070 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1444196 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718048

African (AFR) AF: 0.00 AC: 0 AN: 32658

American (AMR) AF: 0.00 AC: 0 AN: 43168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25840

East Asian (EAS) AF: 0.00 AC: 0 AN: 38654

South Asian (SAS) AF: 0.00 AC: 0 AN: 84514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47582

Middle Eastern (MID) AF: 0.000181 AC: 1 AN: 5528

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1106390

Other (OTH) AF: 0.00 AC: 0 AN: 59862

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152194 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268A>G (p.S90G) alteration is located in exon 1 (coding exon 1) of the ISOC1 gene. This alteration results from a A to G substitution at nucleotide position 268, causing the serine (S) at amino acid position 90 to be replaced by a glycine (G). 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	0.067
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.68	T;T
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	.;N
PhyloP100		1.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-0.39	N;N
REVEL	Benign	0.037
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.047	D;T
Polyphen		0.0	.;B
Vest4		0.087
MutPred		0.42		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);
MVP		0.37
MPC		0.25
ClinPred		0.77	D
GERP RS		3.2
PromoterAI		-0.055	Neutral
Varity_R		0.19
gMVP		0.35
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs1371332498; hg19: chr5-128430727;