Genetic Variant RC3H1:p.Tyr914Cys (chr1-173946833-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_172071.4(RC3H1):c.2741A>G(p.Tyr914Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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

RC3H1
NM_172071.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.58

Variant links:

Genes affected

RC3H1 (HGNC:29434): (ring finger and CCCH-type domains 1) This gene encodes a protein containing RING-type and C3H1-type zinc finger motifs. The encoded protein recognizes and binds to a constitutive decay element (CDE) in the 3' UTR of mRNAs, leading to mRNA deadenylation and degradation. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

RC3H1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.797

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RC3H1	NM_172071.4 link	c.2741A>G	p.Tyr914Cys	missense_variant	Exon 16 of 20	ENST00000367696.7	NP_742068.1	Q5TC82-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RC3H1	ENST00000367696.7 link	c.2741A>G	p.Tyr914Cys	missense_variant	Exon 16 of 20	5	NM_172071.4	ENSP00000356669.2	Q5TC82-1
RC3H1	ENST00000258349.8 link	c.2741A>G	p.Tyr914Cys	missense_variant	Exon 15 of 19	1			Q5TC82-1
RC3H1	ENST00000367694.2 link	c.2741A>G	p.Tyr914Cys	missense_variant	Exon 15 of 19	2		ENSP00000356667.2	Q5TC82-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1434112

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715412

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.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2741A>G (p.Y914C) alteration is located in exon 15 (coding exon 15) of the RC3H1 gene. This alteration results from a A to G substitution at nucleotide position 2741, causing the tyrosine (Y) at amino acid position 914 to be replaced by a cysteine (C). 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

0.11

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;D;.

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D

M_CAP

Benign

0.065

MetaRNN

Pathogenic

0.80

D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.4

M;M;M

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.1

D;D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.86

MVP

0.57

MPC

1.0

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.27

gMVP

0.63

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