rs1274373500

Variant names:

• chr9-101544844-A-C
• rs1274373500
• NM_019592.7:c.706A>C
• RNF20 p.Thr236Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 2 classification points (ACMG Germline Pathogenicity v2019). PM2

The NM_019592.7(RNF20):c.706A>C (p.Thr236Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0000151 (AC=22) in the gnomAD database across 1,461,560 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000101. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: RNF20 NM_019592.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.39
• Publications: 0 publications found

Genes affected

RNF20 (HGNC:10062): (ring finger protein 20) The protein encoded by this gene shares similarity with BRE1 of S. cerevisiae. The protein encoded by this human gene is an E3 ubiquitin ligase that regulates chromosome structure by monoubiquitinating histone H2B. This protein acts as a putative tumor suppressor and positively regulates the p53 tumor suppressor as well as numerous histone H2A and H2B genes. In contrast, this protein also suppresses the expression of several protooncogenes and growth-related genes, including many genes that are induced by epidermal growth factor. This gene selectively suppresses the expression of some genes by interfering with chromatin recruitment of transcription elongation factor SII (TFIIS). [provided by RefSeq, Feb 2012]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AR/unknown gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000101 — very rare for unknown gene (threshold 0.001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_019592.7. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF20 NM_019592.7	MANE Select	c.706A>C p.Thr236Pro	missense	Exon 6 of 20	Prot: NP_062538.5

RNF20 NM_019592.7

MANE Select

HGVSc / HGVSpc.706A>Cp.Thr236Pro

Exon rankExon 6 of 20

missense

Prot: NP_062538.5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	RNF20 ENST00000389120.8	TSL:1MANE Select	c.706A>C p.Thr236Pro	missense	Exon 6 of 20	Prot: ENSP00000373772.3 UniProt:
	RNF20 ENST00000888393.1		c.706A>C p.Thr236Pro	missense	Exon 6 of 20	Prot: ENSP00000558452.1 UniProt:
	RNF20 ENST00000888394.1		c.706A>C p.Thr236Pro	missense	Exon 7 of 21	Prot: ENSP00000558453.1 UniProt:

RNF20 ENST00000389120.8

TSL:1MANE Select

HGVSc / HGVSpc.706A>Cp.Thr236Pro

Exon rankExon 6 of 20

missense

Prot: ENSP00000373772.3UniProt: Q5VTR2

RNF20 ENST00000888393.1

HGVSc / HGVSpc.706A>Cp.Thr236Pro

Exon rankExon 6 of 20

missense

Prot: ENSP00000558452.1UniProt: Q5VTR2

RNF20 ENST00000888394.1

HGVSc / HGVSpc.706A>Cp.Thr236Pro

Exon rankExon 7 of 21

missense

Prot: ENSP00000558453.1UniProt: Q5VTR2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD2 exomes	AF: 0.00000795	AC:2	Hom:	AN:251472	Cov:
GnomAD4 exome	AF: 0.0000151	AC:22	Hom:0	AN:1461560	Cov:30
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 5 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000352	1	28420	0.00	0	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000150	1	66884
SCHEMA(Schizophrenia)	0.0000295	2	67860	0.0000150	2	133312

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	25
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.92	D
FuncVEP CTI	Benign	0.34
GPN-Star LLR	N/A	-8.8
GPN-Star score	N/A	8.8
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.73	T
Mutation Taster	N/A	72/28	polymorphism
MutationAssessor	Benign	1.6	L
PhyloP100	Benign	1.4
popEVE	Benign	-3.7
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Varity_R	N/A	0.26
VESM-3B	Benign	-13

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1274373500;

hg19: chr9-104307126;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar