Genetic Variant NM_002931.4:c.610C>T (chr6-33211312-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_002931.4(RING1):c.610C>T(p.Arg204Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000037 in 1,378,452 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000030 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

RING1
NM_002931.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.53

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAdExome4 at 47 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RING1	NM_002931.4 link	c.610C>T	p.Arg204Cys	missense_variant	Exon 5 of 7	ENST00000374656.5	NP_002922.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RING1	ENST00000374656.5 link	c.610C>T	p.Arg204Cys	missense_variant	Exon 5 of 7	1	NM_002931.4	ENSP00000363787.4		Q06587-1
RING1	ENST00000478431.1 link	n.598C>T		non_coding_transcript_exon_variant	Exon 3 of 5	1

Frequencies

GnomAD3 genomes

AF:

0.0000301

AC:

AN:

132848

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000849

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000777

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

GnomAD3 exomes

AF:

0.0000379

AC:

AN:

237404

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

130542

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000881

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000574

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000377

AC:

AN:

1245526

Hom.:

Cov.:

AF XY:

0.0000421

AC XY:

AN XY:

617294

show subpopulations

Gnomad4 AFR exome

AF:

0.0000739

Gnomad4 AMR exome

AF:

0.0000527

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000484

Gnomad4 SAS exome

AF:

0.0000476

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000369

Gnomad4 OTH exome

AF:

0.0000436

GnomAD4 genome

AF:

0.0000301

AC:

AN:

132926

Hom.:

Cov.:

AF XY:

0.0000156

AC XY:

AN XY:

64066

show subpopulations

Gnomad4 AFR

AF:

0.0000848

Gnomad4 AMR

AF:

0.0000776

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000146

Hom.:

ExAC

AF:

0.0000345

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.610C>T (p.R204C) 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 610, causing the arginine (R) at amino acid position 204 to be replaced by a cysteine (C). 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

0.28

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Benign

-0.15

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

0.18

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.74

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

-0.23

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.52

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.54

MutPred

0.40

Loss of solvent accessibility (P = 3e-04);

MVP

0.80

MPC

0.77

ClinPred

0.20

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over