Genetic Variant INO80C:p.Ser48Ala (chr18-35497733-A-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_194281.4(INO80C):c.142T>G(p.Ser48Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,612,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. 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. S48P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

INO80C
NM_194281.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.124

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.029785067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INO80C	NM_194281.4 link	c.142T>G	p.Ser48Ala	missense_variant	Exon 1 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.142T>G	p.Ser48Ala	missense_variant	Exon 1 of 5	1	NM_194281.4	ENSP00000334473.6		Q6PI98-1
ENSG00000267140	ENST00000589258.1 link	c.142T>G	p.Ser48Ala	missense_variant	Exon 1 of 3	3		ENSP00000467041.1		K7ENP7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1460058

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726286

show subpopulations

Gnomad4 AFR exome

AF:

0.0000900

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:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000193

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 16, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142T>G (p.S48A) alteration is located in exon 1 (coding exon 1) of the INO80C gene. This alteration results from a T to G substitution at nucleotide position 142, causing the serine (S) at amino acid position 48 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

0.059

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.4

DANN

Benign

0.51

DEOGEN2

Benign

0.0066

.;.;T;T;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0094

LIST_S2

Benign

0.39

T;T;T;T;T;T

M_CAP

Benign

0.0030

MetaRNN

Benign

0.030

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

.;L;L;.;L;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.59

.;.;N;.;N;.

REVEL

Benign

0.019

Sift

Benign

0.54

.;.;T;.;T;.

Sift4G

Benign

0.20

T;T;T;T;T;.

Polyphen

0.0010, 0.0

.;B;B;.;.;.

Vest4

0.30

MVP

0.081

MPC

0.0041

ClinPred

0.056

GERP RS

0.28

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.046

gMVP

0.13

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over