chr9-122855773-C-T

Variant names:

• chr9-122855773-C-T
• NM_001100588.3:c.2560G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Moderate BS2

The NM_001100588.3(RC3H2):​c.2560G>A​(p.Glu854Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,460,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.74
• Publications: 0 publications found

Genes affected

RC3H2 (HGNC:21461): (ring finger and CCCH-type domains 2) Enables nucleic acid binding activity and ubiquitin protein ligase activity. Involved in protein polyubiquitination. Located in cell surface; intracellular membrane-bounded organelle; and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09075004).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100588.3. 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
	RC3H2	NM_001100588.3	MANE Select	c.2560G>A	p.Glu854Lys	missense	Exon 14 of 21	NP_001094058.1	Q9HBD1-1
	RC3H2	NM_001354482.2		c.2560G>A	p.Glu854Lys	missense	Exon 14 of 20	NP_001341411.1
	RC3H2	NM_001354479.2		c.2389G>A	p.Glu797Lys	missense	Exon 13 of 20	NP_001341408.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RC3H2	ENST00000357244.7	TSL:5 MANE Select	c.2560G>A	p.Glu854Lys	missense	Exon 14 of 21	ENSP00000349783.2	Q9HBD1-1
	RC3H2	ENST00000373670.5	TSL:5	c.2560G>A	p.Glu854Lys	missense	Exon 13 of 20	ENSP00000362774.1	Q9HBD1-1
	RC3H2	ENST00000954280.1		c.2560G>A	p.Glu854Lys	missense	Exon 15 of 22	ENSP00000624339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1460990 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726808

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111468

Other (OTH) AF: 0.00 AC: 0 AN: 60362

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.0031	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.55
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.063
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.091	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.075	N
PhyloP100		3.7
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.13	B
Vest4		0.31
MutPred		0.34		Gain of ubiquitination at E854 (P = 0.0146)
MVP		0.35
MPC		0.77
ClinPred		0.83	D
GERP RS		5.5
PromoterAI		-0.019	Neutral
Varity_R		0.31
gMVP		0.80
Mutation Taster		=84/16	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

hg19: chr9-125618052;