9-122849794-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.63

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 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/exons	MANE	UniProt
RC3H2	NM_001100588.3	c.3409A>G	p.Thr1137Ala	missense_variant	21/21	ENST00000357244.7
RC3H2	NM_001354482.2	c.3295A>G	p.Thr1099Ala	missense_variant	20/20
RC3H2	NM_001354479.2	c.3238A>G	p.Thr1080Ala	missense_variant	20/20
RC3H2	NM_001354478.2	c.3390A>G	p.Ter1130=	stop_retained_variant	21/21

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RC3H2	ENST00000357244.7	c.3409A>G	p.Thr1137Ala	missense_variant	21/21	5	NM_001100588.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1420020 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 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.: 32

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 03, 2021

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	T
BayesDel_noAF	Benign	-0.48
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.036	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.84	D
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.48	T
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	D
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.

Other links and lift over

hg19: chr9-125612073;