chr5-129094837-G-C

Variant names:

• chr5-129094837-G-C
• rs376439816
• NM_016048.2:c.71G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_016048.2(ISOC1):​c.71G>C​(p.Gly24Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,556,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ISOC1 NM_016048.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.99
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027362734).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ISOC1	NM_016048.2	c.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 5	ENST00000173527.6	NP_057132.2
LOC124901060	XR_007058926.1	n.794C>G		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.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 5	1	NM_016048.2	ENSP00000173527.5
ISOC1	ENST00000514194.5	c.71G>C	p.Gly24Ala	missense_variant	Exon 1 of 3	3		ENSP00000421273.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152114 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000549 AC: 9 AN: 163966 AF XY: 0.0000227

Gnomad AFR exome AF: 0.000777

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000811

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.0000185 AC: 26 AN: 1404820 Hom.: 0 Cov.: 30 AF XY: 0.0000144 AC XY: 10 AN XY: 694116

African (AFR) AF: 0.000466 AC: 15 AN: 32212

American (AMR) AF: 0.00 AC: 0 AN: 36372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25176

East Asian (EAS) AF: 0.0000539 AC: 2 AN: 37082

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5034

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1086192

Other (OTH) AF: 0.000137 AC: 8 AN: 58418

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152114 Hom.: 0 Cov.: 34 AF XY: 0.000161 AC XY: 12 AN XY: 74306

African (AFR) AF: 0.000893 AC: 37 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5152

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000227

ESP6500AA AF: 0.000552 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000684 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.71G>C (p.G24A) alteration is located in exon 1 (coding exon 1) of the ISOC1 gene. This alteration results from a G to C substitution at nucleotide position 71, causing the glycine (G) at amino acid position 24 to be replaced by an alanine (A). 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	0.094
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0090	T;T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.027	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	.;N
PhyloP100		3.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	0.0	N;N
REVEL	Benign	0.055
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.0010	.;B
Vest4		0.25
MVP		0.28
MPC		0.82
ClinPred		0.17	T
GERP RS		3.1
PromoterAI		0.097	Neutral
Varity_R		0.12
gMVP		0.26
Mutation Taster		=91/9	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: rs376439816; hg19: chr5-128430530;