9-122849799-G-T

Variant names:

• chr9-122849799-G-T
• rs764724224
• NM_001100588.3:c.3404C>A

Variant summary

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

The NM_001100588.3(RC3H2):​c.3404C>A​(p.Pro1135Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000212 in 1,414,902 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. P1135R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.41
• 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.3404C>A	p.Pro1135Gln	missense	Exon 21 of 21	NP_001094058.1	Q9HBD1-1
	RC3H2	NM_001354482.2		c.3290C>A	p.Pro1097Gln	missense	Exon 20 of 20	NP_001341411.1
	RC3H2	NM_001354479.2		c.3233C>A	p.Pro1078Gln	missense	Exon 20 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.3404C>A	p.Pro1135Gln	missense	Exon 21 of 21	ENSP00000349783.2	Q9HBD1-1
	RC3H2	ENST00000373670.5	TSL:5	c.3404C>A	p.Pro1135Gln	missense	Exon 20 of 20	ENSP00000362774.1	Q9HBD1-1
	RC3H2	ENST00000954280.1		c.3404C>A	p.Pro1135Gln	missense	Exon 22 of 22	ENSP00000624339.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1414902 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 703246

African (AFR) AF: 0.00 AC: 0 AN: 30910

American (AMR) AF: 0.00 AC: 0 AN: 34172

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24032

East Asian (EAS) AF: 0.00 AC: 0 AN: 38236

South Asian (SAS) AF: 0.00 AC: 0 AN: 78776

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52440

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5530

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092720

Other (OTH) AF: 0.0000172 AC: 1 AN: 58086

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	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Benign	0.038	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.0	N
PhyloP100		6.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.29
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.58
MutPred		0.37		Gain of sheet (P = 0.0221)
MVP		0.74
MPC		0.73
ClinPred		0.76	D
GERP RS		5.6
Varity_R		0.18
gMVP		0.30
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs764724224; hg19: chr9-125612078;