18-35479342-C-G

Variant names:

• chr18-35479342-C-G
• rs769397614
• NM_194281.4:c.337G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_194281.4(INO80C):​c.337G>C​(p.Ala113Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,780 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. A113T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: INO80C NM_194281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.80
• Publications: 0 publications found

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]

ENSG00000267140 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.761

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_194281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INO80C	NM_194281.4	MANE Select	c.337G>C	p.Ala113Pro	missense	Exon 3 of 5	NP_919257.2
	INO80C	NM_001098817.2		c.445G>C	p.Ala149Pro	missense	Exon 5 of 7	NP_001092287.1	Q6PI98-4
	INO80C	NM_001308064.2		c.172G>C	p.Ala58Pro	missense	Exon 3 of 5	NP_001294993.1	K7EIY8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	INO80C	ENST00000334598.12	TSL:1 MANE Select	c.337G>C	p.Ala113Pro	missense	Exon 3 of 5	ENSP00000334473.6	Q6PI98-1
	ENSG00000267140	ENST00000589258.1	TSL:3	c.156+18377G>C		intron	N/A	ENSP00000467041.1	K7ENP7
	INO80C	ENST00000441607.6	TSL:2	c.445G>C	p.Ala149Pro	missense	Exon 5 of 7	ENSP00000391457.1	Q6PI98-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461780 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727182

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111948

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.015	T
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.93
MutPred		0.49		Gain of catalytic residue at A113 (P = 0.0231)
MVP		0.44
MPC		0.55
ClinPred		0.98	D
GERP RS		4.8
Varity_R		0.73
gMVP		0.77
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs769397614; hg19: chr18-33059306; COSMIC: COSV52034779; COSMIC: COSV52034779;