15-40980228-G-A

Variant names:

• chr15-40980228-G-A
• rs151117314
• NM_017553.3:c.4666C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_017553.3(INO80):​c.4666C>T​(p.Arg1556Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000254 in 1,612,388 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000023 (0 hom.)
• Consequence: INO80 NM_017553.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• immunodeficiency, common variable, 1

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

LOC124903476 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14515528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
INO80	NM_017553.3	c.4666C>T	p.Arg1556Trp	missense_variant	Exon 36 of 36	ENST00000648947.1	NP_060023.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
INO80	ENST00000648947.1	c.4666C>T	p.Arg1556Trp	missense_variant	Exon 36 of 36		NM_017553.3	ENSP00000497609.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152234 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251404 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000226 AC: 33 AN: 1460036 Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20 AN XY: 726306

African (AFR) AF: 0.000419 AC: 14 AN: 33410

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86182

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.000448 AC: 2 AN: 4464

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1111764

Other (OTH) AF: 0.0000332 AC: 2 AN: 60246

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152352 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74500

African (AFR) AF: 0.0000241 AC: 1 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000536 Hom.: 2

Bravo AF: 0.0000491

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4666C>T (p.R1556W) alteration is located in exon 36 (coding exon 35) of the INO80 gene. This alteration results from a C to T substitution at nucleotide position 4666, causing the arginine (R) at amino acid position 1556 to be replaced by a tryptophan (W). 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	0.19
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T;T;T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;.;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	0.69	N;N;N;.
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.1	.;N;N;.
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	.;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.41, 0.39, 0.48
MVP		0.20
MPC		1.1
ClinPred		0.31	T
GERP RS		4.5
Varity_R		0.25
gMVP		0.46
Mutation Taster		=86/14	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: rs151117314; hg19: chr15-41272426;