9-122859087-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001100588.3(RC3H2):c.1865C>T(p.Pro622Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000282 in 1,420,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.04

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29441348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RC3H2	NM_001100588.3	c.1865C>T	p.Pro622Leu	missense_variant	12/21	ENST00000357244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RC3H2	ENST00000357244.7	c.1865C>T	p.Pro622Leu	missense_variant	12/21	5	NM_001100588.3	P1
RC3H2	ENST00000373670.5	c.1865C>T	p.Pro622Leu	missense_variant	11/20	5		P1
RC3H2	ENST00000423239.6	c.1865C>T	p.Pro622Leu	missense_variant	12/18	5
RC3H2	ENST00000498479.5	c.*346C>T		3_prime_UTR_variant, NMD_transcript_variant	13/22	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1420800 Hom.: 0 Cov.: 32 AF XY: 0.00000570 AC XY: 4 AN XY: 701506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000256

Gnomad4 SAS exome AF: 0.0000247

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Dec 13, 2023

The c.1865C>T (p.P622L) alteration is located in exon 12 (coding exon 11) of the RC3H2 gene. This alteration results from a C to T substitution at nucleotide position 1865, causing the proline (P) at amino acid position 622 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	0.078
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Benign	-0.35
Cadd	Pathogenic	26
Dann	Uncertain	0.99
DEOGEN2	Benign	0.22	T;T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.29	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.18
Sift4G	Benign	0.071	T;T;T
Polyphen		0.95	P;P;D
Vest4		0.42
MutPred		0.34		Loss of glycosylation at P622 (P = 0.0027);Loss of glycosylation at P622 (P = 0.0027);Loss of glycosylation at P622 (P = 0.0027);
MVP		0.13
MPC		0.77
ClinPred		0.96	D
GERP RS		5.6
Varity_R		0.21
gMVP		0.39

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

Publications

LitVar

Other links and lift over

dbSNP: rs915731081; hg19: chr9-125621366;