Variant 9-122858755-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001100588.3(RC3H2):c.2197C>T(p.Arg733Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,184 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

RC3H2
NM_001100588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.09

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 -4 ACMG points.

BS2

High AC in GnomAdExome at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RC3H2	NM_001100588.3 linkuse as main transcript	c.2197C>T	p.Arg733Trp	missense_variant	12/21	ENST00000357244.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RC3H2	ENST00000357244.7 linkuse as main transcript	c.2197C>T	p.Arg733Trp	missense_variant	12/21	5	NM_001100588.3	P1	Q9HBD1-1
RC3H2	ENST00000373670.5 linkuse as main transcript	c.2197C>T	p.Arg733Trp	missense_variant	11/20	5		P1	Q9HBD1-1
RC3H2	ENST00000423239.6 linkuse as main transcript	c.2197C>T	p.Arg733Trp	missense_variant	12/18	5			Q9HBD1-4
RC3H2	ENST00000498479.5 linkuse as main transcript	c.*678C>T		3_prime_UTR_variant, NMD_transcript_variant	13/22	2			Q9HBD1-2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000240

AC:

AN:

249512

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135364

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461820

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727206

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000331

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

May 13, 2022

The c.2197C>T (p.R733W) 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 2197, causing the arginine (R) at amino acid position 733 to be replaced by a tryptophan (W). 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

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.17

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.17

T;T;.

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.38

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.048

MetaRNN

Uncertain

0.74

D;D;D

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.5

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.3

N;N;N

REVEL

Uncertain

0.38

Sift4G

Uncertain

0.0020

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.93

MutPred

0.56

Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);

MVP

0.78

MPC

0.78

ClinPred

0.50

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.79

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

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