Genetic Variant INO80:p.Arg1246Leu (chr15-40987186-C-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PM5PP3

The NM_017553.3(INO80):c.3737G>T(p.Arg1246Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000659 in 151,690 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R1246Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

INO80
NM_017553.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.78

Variant links:

Genes affected

INO80 (HGNC:26956): (INO80 complex ATPase subunit) This gene encodes a subunit of the chromatin remodeling complex, which is classified into subfamilies depending on sequence features apart from the conserved ATPase domain. This protein is the catalytic ATPase subunit of the INO80 chromatin remodeling complex, which is characterized by a DNA-binding domain. This protein is proposed to bind DNA and be recruited by the YY1 transcription factor to activate certain genes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

INO80 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr15-40987186-C-T is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INO80	NM_017553.3 link	c.3737G>T	p.Arg1246Leu	missense_variant	Exon 31 of 36	ENST00000648947.1	NP_060023.1	Q9ULG1A0A024R9R7
INO80	XM_047432698.1 link	c.3737G>T	p.Arg1246Leu	missense_variant	Exon 31 of 36		XP_047288654.1
INO80	XM_011521686.4 link	c.1787G>T	p.Arg596Leu	missense_variant	Exon 17 of 22		XP_011519988.1
INO80	NR_104038.2 link	n.3960G>T		non_coding_transcript_exon_variant	Exon 30 of 35

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INO80	ENST00000648947.1 link	c.3737G>T	p.Arg1246Leu	missense_variant	Exon 31 of 36		NM_017553.3	ENSP00000497609.1		Q9ULG1

Frequencies

GnomAD3 genomes

AF:

0.00000660

AC:

AN:

151572

Hom.:

Cov.:

show subpopulations

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:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151690

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74190

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000209

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.72

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.040

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T;T;.

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;.;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Benign

1.2

L;L;L;.

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.0

.;D;D;.

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

.;D;D;.

Sift4G

Uncertain

0.0050

.;D;D;D

Polyphen

0.98

D;D;D;.

Vest4

0.78, 0.77, 0.79

MutPred

0.47

Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);Loss of MoRF binding (P = 0.0052);.;

MVP

0.52

MPC

0.87

ClinPred

0.99

GERP RS

4.3

Varity_R

0.72

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Computational scores

Splicing

Publications

Other links and lift over