6-33211285-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_002931.4(RING1):c.583G>A(p.Ala195Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000683 in 1,611,236 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00069 (4 hom.)
• Consequence: RING1 NM_002931.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.633

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0042042136).
• BP6: Variant 6-33211285-G-A is Benign according to our data. Variant chr6-33211285-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2229718.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 98 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RING1	NM_002931.4	c.583G>A	p.Ala195Thr	missense_variant	5/7	ENST00000374656.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RING1	ENST00000374656.5	c.583G>A	p.Ala195Thr	missense_variant	5/7	1	NM_002931.4	P1
RING1	ENST00000478431.1	n.571G>A		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes AF: 0.000660 AC: 100 AN: 151438 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00807

Gnomad EAS AF: 0.000195

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.000919 AC: 225 AN: 244950 Hom.: 1 AF XY: 0.00101 AC XY: 135 AN XY: 133784

Gnomad AFR exome AF: 0.000134

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.00737

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.000922

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000667

Gnomad OTH exome AF: 0.000991

GnomAD4 exome AF: 0.000687 AC: 1003 AN: 1459698 Hom.: 4 Cov.: 33 AF XY: 0.000737 AC XY: 535 AN XY: 726156

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.00112

Gnomad4 ASJ exome AF: 0.00896

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000615

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000473

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000647 AC: 98 AN: 151538 Hom.: 0 Cov.: 31 AF XY: 0.000688 AC XY: 51 AN XY: 74078

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00151

Gnomad4 ASJ AF: 0.00807

Gnomad4 EAS AF: 0.000195

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00113 Hom.: 1

Bravo AF: 0.000759

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000331 AC: 1

ESP6500EA AF: 0.000555 AC: 3

ExAC AF: 0.000861 AC: 101

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00109

EpiControl AF: 0.00119

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 28, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Benign	0.85
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.57	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.94	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	0.73	N
REVEL	Benign	0.072
Sift	Benign	0.61	T
Sift4G	Benign	0.78	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.38
MPC		0.55
ClinPred		0.0047	T
GERP RS		1.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.043
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs149445528; hg19: chr6-33179062; COSMIC: COSV63002273; COSMIC: COSV63002273;