9-122851405-T-A

Variant names:

• chr9-122851405-T-A
• rs558832446
• NM_001100588.3:c.3149A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001100588.3(RC3H2):​c.3149A>T​(p.Asp1050Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. D1050G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.3149A>T	p.Asp1050Val	missense	Exon 19 of 21	NP_001094058.1	Q9HBD1-1
	RC3H2	NM_001354479.2		c.2978A>T	p.Asp993Val	missense	Exon 18 of 20	NP_001341408.1
	RC3H2	NM_001354478.2		c.3149A>T	p.Asp1050Val	missense	Exon 19 of 21	NP_001341407.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RC3H2	ENST00000357244.7	TSL:5 MANE Select	c.3149A>T	p.Asp1050Val	missense	Exon 19 of 21	ENSP00000349783.2	Q9HBD1-1
	RC3H2	ENST00000373670.5	TSL:5	c.3149A>T	p.Asp1050Val	missense	Exon 18 of 20	ENSP00000362774.1	Q9HBD1-1
	RC3H2	ENST00000954280.1		c.3149A>T	p.Asp1050Val	missense	Exon 20 of 22	ENSP00000624339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461852 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112002

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.058	T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
PhyloP100		6.1
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.27
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.39		Loss of solvent accessibility (P = 0.0299)
MVP		0.63
MPC		0.93
ClinPred		0.85	D
GERP RS		5.7
Varity_R		0.44
gMVP		0.33
Mutation Taster		=84/16	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: rs558832446; hg19: chr9-125613684;