Genetic Variant RC3H2:p.Ser952Asn (chr9-122854576-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001100588.3(RC3H2):c.2855G>A(p.Ser952Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000886 in 1,613,592 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: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

RC3H2
NM_001100588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.33

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3894932).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RC3H2	NM_001100588.3 link	c.2855G>A	p.Ser952Asn	missense_variant	Exon 16 of 21	ENST00000357244.7	NP_001094058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RC3H2	ENST00000357244.7 link	c.2855G>A	p.Ser952Asn	missense_variant	Exon 16 of 21	5	NM_001100588.3	ENSP00000349783.2		Q9HBD1-1

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000281

AC:

AN:

249518

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135388

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000618

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000917

AC:

134

AN:

1461414

Hom.:

Cov.:

AF XY:

0.000103

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000907

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000120

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2855G>A (p.S952N) alteration is located in exon 16 (coding exon 15) of the RC3H2 gene. This alteration results from a G to A substitution at nucleotide position 2855, causing the serine (S) at amino acid position 952 to be replaced by an asparagine (N). 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

0.094

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.32

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.069

T;T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

.;T;T

M_CAP

Benign

0.019

MetaRNN

Benign

0.39

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.81

L;L;L

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.19

Sift

Uncertain

0.0020

.;.;D

Sift4G

Uncertain

0.012

D;D;D

Polyphen

0.97

D;D;D

Vest4

0.64

MVP

0.28

MPC

0.68

ClinPred

0.28

GERP RS

5.5

Varity_R

0.55

gMVP

0.76

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