chr5-129105192-G-C

Variant names:

• chr5-129105192-G-C
• rs762370649
• NM_016048.2:c.437G>C

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.437G>C​(p.Gly146Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. G146E) 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: 5.61
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26328242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2	c.437G>C	p.Gly146Ala	missense_variant	Exon 3 of 5	ENST00000173527.6	NP_057132.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ISOC1	ENST00000173527.6	c.437G>C	p.Gly146Ala	missense_variant	Exon 3 of 5	1	NM_016048.2	ENSP00000173527.5
ISOC1	ENST00000514194.5	c.410G>C	p.Gly137Ala	missense_variant	Exon 3 of 3	3		ENSP00000421273.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461326 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726966

African (AFR) AF: 0.00 AC: 0 AN: 33414

American (AMR) AF: 0.00 AC: 0 AN: 44664

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26108

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86174

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111768

Other (OTH) AF: 0.00 AC: 0 AN: 60356

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Benign	0.72
DEOGEN2	Benign	0.0053	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0085	T
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.66	.;N
PhyloP100		5.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	1.8	N;N
REVEL	Benign	0.17
Sift	Benign	0.57	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.046	.;B
Vest4		0.37
MutPred		0.53		.;Gain of MoRF binding (P = 0.1733);
MVP		0.61
MPC		0.31
ClinPred		0.70	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.76
Mutation Taster		=57/43	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: rs762370649; hg19: chr5-128440885;