Genetic Variant INO80C:p.Gly53Ser (chr18-35480563-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_194281.4(INO80C):c.157G>A(p.Gly53Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,448,152 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G53D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

INO80C
NM_194281.4 missense, splice_region

Scores

Splicing: ADA: 0.5785

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.00

Variant links:

Genes affected

INO80C (HGNC:26994): (INO80 complex subunit C) Predicted to be involved in chromatin remodeling. Part of Ino80 complex and MLL1 complex. [provided by Alliance of Genome Resources, Apr 2022]

INO80C links:

ENSG00000267140 (HGNC:):

ENSG00000267140 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1043528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INO80C	NM_194281.4 link	c.157G>A	p.Gly53Ser	missense_variant, splice_region_variant	Exon 2 of 5	ENST00000334598.12	NP_919257.2	Q6PI98-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INO80C	ENST00000334598.12 link	c.157G>A	p.Gly53Ser	missense_variant, splice_region_variant	Exon 2 of 5	1	NM_194281.4	ENSP00000334473.6		Q6PI98-1
ENSG00000267140	ENST00000589258.1 link	c.156+17156G>A		intron_variant	Intron 1 of 2	3		ENSP00000467041.1		K7ENP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.91e-7

AC:

AN:

1448152

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721512

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.10e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.265G>A (p.G89S) alteration is located in exon 4 (coding exon 4) of the INO80C gene. This alteration results from a G to A substitution at nucleotide position 265, causing the glycine (G) at amino acid position 89 to be replaced by a serine (S). 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

0.087

BayesDel_addAF

Benign

-0.0077

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.0045

.;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.71

T;T;T

M_CAP

Benign

0.028

MetaRNN

Benign

0.072

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

L;L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.32

.;N;N

REVEL

Benign

0.13

Sift

Benign

0.33

.;T;D

Sift4G

Benign

0.77

T;T;D

Polyphen

0.87

P;P;.

Vest4

0.21

MutPred

0.074

Gain of phosphorylation at G53 (P = 0.0185);Gain of phosphorylation at G53 (P = 0.0185);.;

MVP

0.21

MPC

0.38

ClinPred

0.90

GERP RS

5.0

Varity_R

0.090

gMVP

0.16

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.58

dbscSNV1_RF

Benign

0.44

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.31

Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over