rs5749088

Variant names:

• chr22-30380106-C-T
• rs5749088
• NM_001017981.2:c.964G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

The NM_001017981.2(RNF215):​c.964G>A​(p.Ala322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,613,820 control chromosomes in the GnomAD database, including 40,898 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2979 hom., cov: 32)
  • Exomes 𝑓: 0.22 (37919 hom.)
• Consequence: RNF215 NM_001017981.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0250
• Publications: 40 publications found

Genes affected

RNF215 (HGNC:33434): (ring finger protein 215) Predicted to enable ubiquitin protein ligase activity. Predicted to be involved in Golgi to vacuole transport; protein targeting to vacuole; and ubiquitin-dependent protein catabolic process. Predicted to be integral component of membrane. Predicted to be part of Golgi transport complex. Predicted to be active in endosome; membrane; and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.238 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF215	NM_001017981.2	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 9	ENST00000382363.8	NP_001017981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF215	ENST00000382363.8	c.964G>A	p.Ala322Thr	missense_variant	Exon 7 of 9	1	NM_001017981.2	ENSP00000371800.3
RNF215	ENST00000215798.10	c.775G>A	p.Ala259Thr	missense_variant	Exon 7 of 8	5		ENSP00000215798.6
RNF215	ENST00000463319.1	n.716G>A		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27653 AN: 152036 Hom.: 2980 Cov.: 32

Gnomad AFR AF: 0.0835

Gnomad AMI AF: 0.180

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.133

Gnomad SAS AF: 0.0957

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.191 AC: 48009 AN: 251062 AF XY: 0.195

Gnomad AFR exome AF: 0.0796

Gnomad AMR exome AF: 0.138

Gnomad ASJ exome AF: 0.313

Gnomad EAS exome AF: 0.143

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.246

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.221 AC: 323406 AN: 1461666 Hom.: 37919 Cov.: 33 AF XY: 0.219 AC XY: 159338 AN XY: 727162

African (AFR) AF: 0.0794 AC: 2659 AN: 33478

American (AMR) AF: 0.143 AC: 6410 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 8091 AN: 26130

East Asian (EAS) AF: 0.109 AC: 4317 AN: 39698

South Asian (SAS) AF: 0.110 AC: 9470 AN: 86256

European-Finnish (FIN) AF: 0.161 AC: 8559 AN: 53274

Middle Eastern (MID) AF: 0.262 AC: 1511 AN: 5768

European-Non Finnish (NFE) AF: 0.242 AC: 268980 AN: 1111956

Other (OTH) AF: 0.222 AC: 13409 AN: 60390

GnomAD4 genome AF: 0.182 AC: 27648 AN: 152154 Hom.: 2979 Cov.: 32 AF XY: 0.176 AC XY: 13085 AN XY: 74378

African (AFR) AF: 0.0835 AC: 3468 AN: 41532

American (AMR) AF: 0.205 AC: 3132 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.313 AC: 1087 AN: 3470

East Asian (EAS) AF: 0.133 AC: 687 AN: 5166

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4824

European-Finnish (FIN) AF: 0.156 AC: 1656 AN: 10608

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.242 AC: 16409 AN: 67944

Other (OTH) AF: 0.230 AC: 485 AN: 2112

Alfa AF: 0.233 Hom.: 12605

Bravo AF: 0.184

TwinsUK AF: 0.234 AC: 867

ALSPAC AF: 0.252 AC: 973

ESP6500AA AF: 0.0840 AC: 370

ESP6500EA AF: 0.256 AC: 2198

ExAC AF: 0.189 AC: 22999

Asia WGS AF: 0.128 AC: 447 AN: 3478

EpiCase AF: 0.265

EpiControl AF: 0.272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	15
DANN	Benign	0.89
DEOGEN2	Benign	0.0081	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.17	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.025
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.036
Sift	Benign	0.35	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.018
MPC		0.34
ClinPred		0.0023	T
GERP RS		-6.3
PromoterAI		0.018	Neutral
Varity_R		0.027
gMVP		0.18
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.81		Position offset: 3

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

Other links and lift over

dbSNP: rs5749088; hg19: chr22-30776095; COSMIC: COSV53176131; COSMIC: COSV53176131;