Genetic Variant RING1:p.Thr243Met (chr6-33211430-C-T) – 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.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

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.99

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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.33173275).

BS2

High AC in GnomAd4 at 10 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.728C>T	p.Thr243Met	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.728C>T	p.Thr243Met	missense	Exon 5 of 7	ENSP00000363787.4	Q06587-1
RING1	ENST00000478431.1	TSL:1	n.716C>T		non_coding_transcript_exon	Exon 3 of 5
RING1	ENST00000869802.1		c.728C>T	p.Thr243Met	missense	Exon 4 of 6	ENSP00000539861.1

Frequencies

GnomAD3 genomes

AF:

0.0000659

AC:

AN:

151728

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000553

AC:

AN:

180794

AF XY:

0.0000601

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000797

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1421480

Hom.:

Cov.:

AF XY:

0.0000199

AC XY:

AN XY:

704714

show subpopulations

African (AFR)

AF:

0.0000924

AC:

AN:

32482

American (AMR)

AF:

0.0000786

AC:

AN:

38186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25192

East Asian (EAS)

AF:

0.0000267

AC:

AN:

37424

South Asian (SAS)

AF:

0.00

AC:

AN:

82740

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49078

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5588

European-Non Finnish (NFE)

AF:

0.0000247

AC:

AN:

1091958

Other (OTH)

AF:

0.0000510

AC:

AN:

58832

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.0000659

AC:

AN:

151844

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74224

show subpopulations

African (AFR)

AF:

0.0000483

AC:

AN:

41430

American (AMR)

AF:

0.0000655

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5108

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

67854

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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:

0.0000851

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000614

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

0.15

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.10

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.81

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.33

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

0.0

PhyloP100

2.0

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.4

REVEL

Uncertain

0.36

Sift

Benign

0.10

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.34

MutPred

0.15

Loss of glycosylation at T243 (P = 0.0025)

MVP

0.77

MPC

0.59

ClinPred

0.071

GERP RS

4.2

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.3

Varity_R

0.052

gMVP

0.24

Mutation Taster

=90/10

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

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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