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GeneBe

6-33211430-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_002931.4(RING1):c.728C>T(p.Thr243Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,573,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

RING1
NM_002931.4 missense

Scores

1
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99
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 -5 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.33173275).
BS2
High AC in GnomAd at 10 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RING1NM_002931.4 linkuse as main transcriptc.728C>T p.Thr243Met missense_variant 5/7 ENST00000374656.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RING1ENST00000374656.5 linkuse as main transcriptc.728C>T p.Thr243Met missense_variant 5/71 NM_002931.4 P1Q06587-1
RING1ENST00000478431.1 linkuse as main transcriptn.716C>T non_coding_transcript_exon_variant 3/51

Frequencies

GnomAD3 genomes
AF:
0.0000659
AC:
10
AN:
151728
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000484
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000656
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:
0.000103
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000553
AC:
10
AN:
180794
Hom.:
0
AF XY:
0.0000601
AC XY:
6
AN XY:
99860
show subpopulations
Gnomad AFR exome
AF:
0.000106
Gnomad AMR exome
AF:
0.0000739
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000760
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000797
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000260
AC:
37
AN:
1421480
Hom.:
0
Cov.:
37
AF XY:
0.0000199
AC XY:
14
AN XY:
704714
show subpopulations
Gnomad4 AFR exome
AF:
0.0000924
Gnomad4 AMR exome
AF:
0.0000786
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000267
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000247
Gnomad4 OTH exome
AF:
0.0000510
GnomAD4 genome
AF:
0.0000659
AC:
10
AN:
151844
Hom.:
0
Cov.:
32
AF XY:
0.0000808
AC XY:
6
AN XY:
74224
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000103
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000851
Hom.:
0
Bravo
AF:
0.0000529
ExAC
AF:
0.0000614
AC:
7

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 GeneticsAug 23, 2021The c.728C>T (p.T243M) alteration is located in exon 5 (coding exon 4) of the RING1 gene. This alteration results from a C to T substitution at nucleotide position 728, causing the threonine (T) at amino acid position 243 to be replaced by a methionine (M). 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
0.15
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Benign
-0.11
Cadd
Uncertain
23
Dann
Uncertain
0.99
DEOGEN2
Benign
0.10
T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.81
D
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.33
T
MetaSVM
Uncertain
0.24
D
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
0.51
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-1.4
N
REVEL
Uncertain
0.36
Sift
Benign
0.10
T
Sift4G
Benign
0.14
T
Polyphen
1.0
D
Vest4
0.34
MutPred
0.15
Loss of glycosylation at T243 (P = 0.0025);
MVP
0.77
MPC
0.59
ClinPred
0.071
T
GERP RS
4.2
RBP_binding_hub_radar
1.1
RBP_regulation_power_radar
2.3
Varity_R
0.052
gMVP
0.24

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: rs758957921; hg19: chr6-33179207; COSMIC: COSV63002724; COSMIC: COSV63002724; API