9-122857930-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001100588.3(RC3H2):c.2447G>T(p.Arg816Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,116 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R816H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.83

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19075778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RC3H2	NM_001100588.3	c.2447G>T	p.Arg816Leu	missense_variant	13/21	ENST00000357244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RC3H2	ENST00000357244.7	c.2447G>T	p.Arg816Leu	missense_variant	13/21	5	NM_001100588.3	P1
RC3H2	ENST00000373670.5	c.2447G>T	p.Arg816Leu	missense_variant	12/20	5		P1
RC3H2	ENST00000423239.6	c.2447G>T	p.Arg816Leu	missense_variant	13/18	5
RC3H2	ENST00000498479.5	c.*928G>T		3_prime_UTR_variant, NMD_transcript_variant	14/22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460116 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726310

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 16, 2023

The c.2447G>T (p.R816L) alteration is located in exon 13 (coding exon 12) of the RC3H2 gene. This alteration results from a G to T substitution at nucleotide position 2447, causing the arginine (R) at amino acid position 816 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	21
Dann	Benign	0.90
DEOGEN2	Benign	0.023	T;T;.
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.058
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.19	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;N
MutationTaster	Benign	0.53	D;D;D;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.20	N;N;N
REVEL	Benign	0.15
Sift4G	Benign	0.66	T;T;T
Polyphen		0.089	B;B;B
Vest4		0.55
MVP		0.51
MPC		0.26
ClinPred		0.57	D
GERP RS		5.8
Varity_R		0.19
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs368828068; hg19: chr9-125620209;