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GeneBe

6-33211888-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_002931.4(RING1):c.1005G>C(p.Glu335Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,606,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

RING1
NM_002931.4 missense

Scores

3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.896
Variant links:
Genes affected
RING1 (HGNC:10018): (ring finger protein 1) This gene belongs to the RING finger family, members of which encode proteins characterized by a RING domain, a zinc-binding motif related to the zinc finger domain. The gene product can bind DNA and can act as a transcriptional repressor. It is associated with the multimeric polycomb group protein complex. The gene product interacts with the polycomb group proteins BMI1, EDR1, and CBX4, and colocalizes with these proteins in large nuclear domains. It interacts with the CBX4 protein via its glycine-rich C-terminal domain. The gene maps to the HLA class II region, where it is contiguous with the RING finger genes FABGL and HKE4. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.19208154).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RING1NM_002931.4 linkuse as main transcriptc.1005G>C p.Glu335Asp missense_variant 6/7 ENST00000374656.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RING1ENST00000374656.5 linkuse as main transcriptc.1005G>C p.Glu335Asp missense_variant 6/71 NM_002931.4 P1Q06587-1
RING1ENST00000478431.1 linkuse as main transcriptn.993G>C non_coding_transcript_exon_variant 4/51

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000413
AC:
6
AN:
1454430
Hom.:
0
Cov.:
38
AF XY:
0.00000276
AC XY:
2
AN XY:
723330
show subpopulations
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:
0.00000541
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152192
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

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 GeneticsMay 23, 2023The c.1005G>C (p.E335D) alteration is located in exon 6 (coding exon 5) of the RING1 gene. This alteration results from a G to C substitution at nucleotide position 1005, causing the glutamic acid (E) at amino acid position 335 to be replaced by an aspartic acid (D). 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
0.072
BayesDel_addAF
Benign
-0.010
T
BayesDel_noAF
Benign
-0.25
Cadd
Benign
19
Dann
Uncertain
0.99
DEOGEN2
Benign
0.065
T
Eigen
Benign
-0.30
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.78
D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
0.90
N
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.38
N
REVEL
Benign
0.21
Sift
Benign
0.039
D
Sift4G
Benign
0.57
T
Polyphen
0.64
P
Vest4
0.35
MutPred
0.15
Gain of relative solvent accessibility (P = 0.09);
MVP
0.58
MPC
0.51
ClinPred
0.42
T
GERP RS
3.2
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
3.7
Varity_R
0.069
gMVP
0.29

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.

Other links and lift over

dbSNP: rs890242891; hg19: chr6-33179665; API