Genetic Variant RC3H2:p.Thr1137Ala (chr9-122849794-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001100588.3(RC3H2):c.3409A>G(p.Thr1137Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

RC3H2
NM_001100588.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.63

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:

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ACMG classification

Classification made for transcript

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=0.1282979).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
RC3H2	NM_001100588.3 link	c.3409A>G	p.Thr1137Ala	missense_variant	Exon 21 of 21	ENST00000357244.7	NP_001094058.1
RC3H2	NM_001354482.2 link	c.3295A>G	p.Thr1099Ala	missense_variant	Exon 20 of 20		NP_001341411.1
RC3H2	NM_001354479.2 link	c.3238A>G	p.Thr1080Ala	missense_variant	Exon 20 of 20		NP_001341408.1
RC3H2	NM_001354478.2 link	c.3390A>G	p.Ter1130Ter	stop_retained_variant	Exon 21 of 21		NP_001341407.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RC3H2	ENST00000357244.7 link	c.3409A>G	p.Thr1137Ala	missense_variant	Exon 21 of 21	5	NM_001100588.3	ENSP00000349783.2		Q9HBD1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1420020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

706020

Gnomad4 AFR exome

AF:

0.00

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3409A>G (p.T1137A) alteration is located in exon 21 (coding exon 20) of the RC3H2 gene. This alteration results from a A to G substitution at nucleotide position 3409, causing the threonine (T) at amino acid position 1137 to be replaced by an alanine (A). 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

0.062

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.036

T;T

Eigen

Benign

-0.20

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.69

.;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.48

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.090

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.0

B;B

Vest4

0.28

MutPred

0.26

Gain of catalytic residue at T1137 (P = 0.0785);Gain of catalytic residue at T1137 (P = 0.0785);

MVP

0.65

MPC

0.54

ClinPred

0.96

GERP RS

4.4

Varity_R

0.11

gMVP

0.39

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over