4-75482647-T-C

Variant summary

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

The NM_015436.4(RCHY1):ā€‹c.677A>Gā€‹(p.Asn226Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,454,832 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

RCHY1
NM_015436.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.77
Variant links:
Genes affected
RCHY1 (HGNC:17479): (ring finger and CHY zinc finger domain containing 1) The protein encoded by this gene has ubiquitin ligase activity. It mediates E3-dependent ubiquitination and proteasomal degradation of target proteins, including tumor protein 53, histone deacetylase 1, and cyclin-dependent kinase inhibitor 1B, thus regulating their levels and cell cycle progression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2013]

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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=0.10725331).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RCHY1NM_015436.4 linkc.677A>G p.Asn226Ser missense_variant 9/9 ENST00000324439.10 NP_056251.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RCHY1ENST00000324439.10 linkc.677A>G p.Asn226Ser missense_variant 9/91 NM_015436.4 ENSP00000321239.5 Q96PM5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247518
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133862
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000298
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1454832
Hom.:
0
Cov.:
28
AF XY:
0.00000276
AC XY:
2
AN XY:
723798
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000455
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

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 submitterclinical testingAmbry GeneticsApr 25, 2022The c.677A>G (p.N226S) alteration is located in exon 9 (coding exon 9) of the RCHY1 gene. This alteration results from a A to G substitution at nucleotide position 677, causing the asparagine (N) at amino acid position 226 to be replaced by a serine (S). 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
0.065
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.68
CADD
Benign
21
DANN
Benign
0.95
DEOGEN2
Benign
0.24
T;.;.;.;.
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.073
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.97
D;D;D;D;D
M_CAP
Benign
0.0049
T
MetaRNN
Benign
0.11
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.14
N;.;.;.;.
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-2.0
N;N;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.13
T;T;T;T;T
Sift4G
Benign
0.38
T;T;T;T;T
Polyphen
0.0010
B;.;.;B;.
Vest4
0.16
MutPred
0.53
Gain of catalytic residue at N223 (P = 0.1401);.;.;.;.;
MVP
0.11
MPC
0.37
ClinPred
0.30
T
GERP RS
4.7
Varity_R
0.044
gMVP
0.064

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs764896720; hg19: chr4-76407857; API