Genetic Variant RING1:p.Gly209Ala (chr6-33211328-G-C) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_002931.4(RING1):c.626G>C(p.Gly209Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000286 in 1,610,026 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. G209E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

RING1
NM_002931.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.94

Publications

1 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2697277).

BS2

High AC in GnomAd4 at 7 AD,Unknown gene.

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.626G>C	p.Gly209Ala	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.626G>C	p.Gly209Ala	missense	Exon 5 of 7	ENSP00000363787.4	Q06587-1
RING1	ENST00000478431.1	TSL:1	n.614G>C		non_coding_transcript_exon	Exon 3 of 5
RING1	ENST00000869802.1		c.626G>C	p.Gly209Ala	missense	Exon 4 of 6	ENSP00000539861.1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151886

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.0000298

AC:

AN:

234822

AF XY:

0.0000309

show subpopulations

Gnomad AFR exome

AF:

0.0000738

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1458140

Hom.:

Cov.:

AF XY:

0.0000290

AC XY:

AN XY:

725254

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33422

American (AMR)

AF:

0.0000451

AC:

AN:

44380

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39646

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86116

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5284

European-Non Finnish (NFE)

AF:

0.0000243

AC:

AN:

1110844

Other (OTH)

AF:

0.0000166

AC:

AN:

60200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.0000461

AC:

AN:

151886

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

74174

show subpopulations

African (AFR)

AF:

0.0000968

AC:

AN:

41338

American (AMR)

AF:

0.000131

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5126

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67916

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

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.:

ExAC

AF:

0.0000432

AC:

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

0.081

BayesDel_addAF

Benign

-0.0093

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.044

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.72

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.27

MetaSVM

Uncertain

0.25

MutationAssessor

Benign

0.0

PhyloP100

3.9

PrimateAI

Uncertain

0.73

PROVEAN

Benign

0.71

REVEL

Uncertain

0.32

Sift

Benign

0.79

Sift4G

Benign

0.98

Polyphen

1.0

Vest4

0.23

MutPred

0.28

Loss of relative solvent accessibility (P = 0.0306)

MVP

0.91

MPC

0.61

ClinPred

0.077

GERP RS

4.3

Varity_R

0.11

gMVP

0.37

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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