Genetic Variant RING1:p.Arg235Leu (chr6-33211406-G-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_002931.4(RING1):c.704G>T(p.Arg235Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000256 in 1,560,552 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R235Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

RING1
NM_002931.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.64

Publications

0 publications found

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]

RING1 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Illumina, Ambry Genetics

RING1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.39335778).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002931.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RING1	NM_002931.4	MANE Select	c.704G>T	p.Arg235Leu	missense	Exon 5 of 7	NP_002922.2	A0A1U9X8F2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RING1	ENST00000374656.5	TSL:1 MANE Select	c.704G>T	p.Arg235Leu	missense	Exon 5 of 7	ENSP00000363787.4	Q06587-1
RING1	ENST00000478431.1	TSL:1	n.692G>T		non_coding_transcript_exon	Exon 3 of 5
RING1	ENST00000869802.1		c.704G>T	p.Arg235Leu	missense	Exon 4 of 6	ENSP00000539861.1

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151592

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.10e-7

AC:

AN:

1408960

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

697164

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32072

American (AMR)

AF:

0.00

AC:

AN:

36454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24974

East Asian (EAS)

AF:

0.00

AC:

AN:

36480

South Asian (SAS)

AF:

0.00

AC:

AN:

81584

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48008

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085574

Other (OTH)

AF:

0.0000171

AC:

AN:

58326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151592

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74048

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41280

American (AMR)

AF:

0.000197

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67800

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.059

BayesDel_noAF

Benign

-0.15

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

0.037

Eigen_PC

Benign

0.17

FATHMM_MKL

Uncertain

0.88

M_CAP

Benign

0.037

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.0

PhyloP100

4.6

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.94

REVEL

Uncertain

0.36

Sift

Benign

0.12

Sift4G

Benign

0.30

Polyphen

0.66

Vest4

0.56

MutPred

0.19

Loss of phosphorylation at T238 (P = 0.0521)

MVP

0.78

MPC

0.71

ClinPred

0.55

GERP RS

4.3

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.3

Varity_R

0.17

gMVP

0.31

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over