5-180013074-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_018434.6(RNF130):c.680G>A(p.Arg227His) variant causes a missense change. The variant allele was found at a frequency of 0.000137 in 1,613,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RNF130 NM_018434.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.04

Genes affected

RNF130 (HGNC:18280): (ring finger protein 130) The protein encoded by this gene contains a RING finger motif and is similar to g1, a Drosophila zinc-finger protein that is expressed in mesoderm and involved in embryonic development. The expression of the mouse counterpart was found to be upregulated in myeloblastic cells following IL3 deprivation, suggesting that this gene may regulate growth factor withdrawal-induced apoptosis of myeloid precursor cells. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17679468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF130	NM_018434.6	c.680G>A	p.Arg227His	missense_variant	3/9	ENST00000521389.6
RNF130	NM_001410829.1	c.680G>A	p.Arg227His	missense_variant	3/8
RNF130	NM_001280801.2	c.680G>A	p.Arg227His	missense_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF130	ENST00000521389.6	c.680G>A	p.Arg227His	missense_variant	3/9	1	NM_018434.6	P4
RNF130	ENST00000261947.4	c.680G>A	p.Arg227His	missense_variant	3/8	1		A2
RNF130	ENST00000520911.5	c.*199G>A		3_prime_UTR_variant, NMD_transcript_variant	3/9	1
RNF130	ENST00000522208.6	c.680G>A	p.Arg227His	missense_variant	3/8	5		A1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000878 AC: 22 AN: 250564 Hom.: 0 AF XY: 0.0000886 AC XY: 12 AN XY: 135504

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000140 AC: 204 AN: 1461100 Hom.: 0 Cov.: 31 AF XY: 0.000131 AC XY: 95 AN XY: 726886

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000171

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152088 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74308

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000215 Hom.: 0

Bravo AF: 0.000136

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

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

May 23, 2023

The c.680G>A (p.R227H) alteration is located in exon 3 (coding exon 3) of the RNF130 gene. This alteration results from a G to A substitution at nucleotide position 680, causing the arginine (R) at amino acid position 227 to be replaced by a histidine (H). 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	Uncertain	0.39
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.39
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.015	D;D;D
Sift4G	Benign	0.12	T;T;D
Polyphen		0.80	.;P;.
Vest4		0.20
MVP		0.24
MPC		1.0
ClinPred		0.20	T
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.80

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs373824991; hg19: chr5-179440074; COSMIC: COSV56150756; COSMIC: COSV56150756;