6-33211462-A-C

Position:

• chr6-33211462-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_002931.4(RING1):​c.760A>C​(p.Ser254Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RING1 NM_002931.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.91

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 Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity RING1_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24672374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RING1	NM_002931.4	c.760A>C	p.Ser254Arg	missense_variant	5/7	ENST00000374656.5	NP_002922.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RING1	ENST00000374656.5	c.760A>C	p.Ser254Arg	missense_variant	5/7	1	NM_002931.4	ENSP00000363787	P1
RING1	ENST00000478431.1	n.748A>C		non_coding_transcript_exon_variant	3/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 22, 2021

The c.760A>C (p.S254R) alteration is located in exon 5 (coding exon 4) of the RING1 gene. This alteration results from a A to C substitution at nucleotide position 760, causing the serine (S) at amino acid position 254 to be replaced by an arginine (R). 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	0.21
BayesDel_addAF	Benign	0.0012	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.030
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.76	N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.29
Sift	Benign	0.20	T
Sift4G	Benign	0.32	T
Polyphen		0.65	P
Vest4		0.23
MutPred		0.30		Loss of phosphorylation at S254 (P = 0.0034);
MVP		0.74
MPC		0.64
ClinPred		0.65	D
GERP RS		4.2
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.9
Varity_R		0.097
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33179239;