9-101550624-G-T

Position:

• chr9-101550624-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_019592.7(RNF20):​c.1111G>T​(p.Val371Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,126 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00075 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: RNF20 NM_019592.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.33

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0147533715).
• BS2: High AC in GnomAd4 at 114 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF20	NM_019592.7	c.1111G>T	p.Val371Leu	missense_variant	10/20	ENST00000389120.8	NP_062538.5
RNF20	XM_011518862.2	c.1111G>T	p.Val371Leu	missense_variant	10/20		XP_011517164.1
RNF20	XM_047423594.1	c.1111G>T	p.Val371Leu	missense_variant	11/21		XP_047279550.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF20	ENST00000389120.8	c.1111G>T	p.Val371Leu	missense_variant	10/20	1	NM_019592.7	ENSP00000373772.3

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152192 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000330 AC: 83 AN: 251302 Hom.: 0 AF XY: 0.000295 AC XY: 40 AN XY: 135806

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000133 AC: 195 AN: 1461816 Hom.: 1 Cov.: 31 AF XY: 0.000121 AC XY: 88 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152310 Hom.: 3 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74468

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000108 Hom.: 0

Bravo AF: 0.000672

ExAC AF: 0.000148 AC: 18

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

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

Dec 07, 2021

The c.1111G>T (p.V371L) alteration is located in exon 10 (coding exon 9) of the RNF20 gene. This alteration results from a G to T substitution at nucleotide position 1111, causing the valine (V) at amino acid position 371 to be replaced by a leucine (L). 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	0.26
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.096	T
Sift4G	Uncertain	0.059	T
Polyphen		0.46	P
Vest4		0.42
MutPred		0.31		Loss of ubiquitination at K376 (P = 0.1465);
MVP		0.51
MPC		0.64
ClinPred		0.079	T
GERP RS		5.9
Varity_R		0.19
gMVP		0.52

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

Other links and lift over

dbSNP: rs189985748; hg19: chr9-104312906;