Variant 9-122857930-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001100588.3(RC3H2):c.2447G>A(p.Arg816His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 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. R816L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

RC3H2
NM_001100588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.83

Variant links:

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]

RC3H2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13295704).

BS2

High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RC3H2	NM_001100588.3 linkuse as main transcript	c.2447G>A	p.Arg816His	missense_variant	13/21	ENST00000357244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RC3H2	ENST00000357244.7 linkuse as main transcript	c.2447G>A	p.Arg816His	missense_variant	13/21	5	NM_001100588.3	P1	Q9HBD1-1
RC3H2	ENST00000373670.5 linkuse as main transcript	c.2447G>A	p.Arg816His	missense_variant	12/20	5		P1	Q9HBD1-1
RC3H2	ENST00000423239.6 linkuse as main transcript	c.2447G>A	p.Arg816His	missense_variant	13/18	5			Q9HBD1-4
RC3H2	ENST00000498479.5 linkuse as main transcript	c.*928G>A		3_prime_UTR_variant, NMD_transcript_variant	14/22	2			Q9HBD1-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247538

Hom.:

AF XY:

0.00000745

AC XY:

AN XY:

134244

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000279

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460116

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

726310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000903

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:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.2447G>A (p.R816H) alteration is located in exon 13 (coding exon 12) of the RC3H2 gene. This alteration results from a G to A substitution at nucleotide position 2447, causing the arginine (R) at amino acid position 816 to be replaced by a histidine (H). 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

0.069

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.40

Cadd

Benign

Dann

Benign

0.86

DEOGEN2

Benign

0.022

T;T;.

Eigen

Benign

-0.13

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.92

M_CAP

Benign

0.0060

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

N;N;N

MutationTaster

Benign

0.69

N;N;N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-0.76

N;N;N

REVEL

Benign

0.12

Sift4G

Benign

0.55

T;T;T

Polyphen

0.43

B;B;B

Vest4

0.45

MutPred

0.35

Gain of glycosylation at S812 (P = 0.1005);Gain of glycosylation at S812 (P = 0.1005);Gain of glycosylation at S812 (P = 0.1005);

MVP

0.56

MPC

0.29

ClinPred

0.11

GERP RS

5.8

Varity_R

0.19

gMVP

0.20

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over