chr2-85597128-T-C

Position:

• chr2-85597128-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016494.4(RNF181):​c.352T>C​(p.Tyr118His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0606 in 1,613,934 control chromosomes in the GnomAD database, including 11,317 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.16 (4592 hom., cov: 32)
  • Exomes 𝑓: 0.050 (6725 hom.)
• Consequence: RNF181 NM_016494.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.65

Genes affected

RNF181 (HGNC:28037): (ring finger protein 181) RNF181 binds the integrin alpha-IIb (ITGA2B; MIM 607759)/beta-3 (ITGB3; MIM 173470) complex and has E3 ubiquitin ligase activity (Brophy et al., 2008 [PubMed 18331836]).[supplied by OMIM, Dec 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.598698E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF181	NM_016494.4	c.352T>C	p.Tyr118His	missense_variant	4/5	ENST00000306368.9	NP_057578.1
RNF181	XM_005264359.5	c.393T>C	p.Ala131Ala	synonymous_variant	3/4		XP_005264416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF181	ENST00000306368.9	c.352T>C	p.Tyr118His	missense_variant	4/5	1	NM_016494.4	ENSP00000306906.4

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24510 AN: 151970 Hom.: 4574 Cov.: 32

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0828

Gnomad ASJ AF: 0.0323

Gnomad EAS AF: 0.318

Gnomad SAS AF: 0.0747

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.0900 AC: 22634 AN: 251456 Hom.: 2869 AF XY: 0.0799 AC XY: 10861 AN XY: 135904

Gnomad AFR exome AF: 0.459

Gnomad AMR exome AF: 0.0786

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.304

Gnomad SAS exome AF: 0.0592

Gnomad FIN exome AF: 0.0552

Gnomad NFE exome AF: 0.0276

Gnomad OTH exome AF: 0.0624

GnomAD4 exome AF: 0.0501 AC: 73260 AN: 1461846 Hom.: 6725 Cov.: 33 AF XY: 0.0486 AC XY: 35350 AN XY: 727236

Gnomad4 AFR exome AF: 0.458

Gnomad4 AMR exome AF: 0.0792

Gnomad4 ASJ exome AF: 0.0334

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.0629

Gnomad4 FIN exome AF: 0.0571

Gnomad4 NFE exome AF: 0.0249

Gnomad4 OTH exome AF: 0.0734

GnomAD4 genome AF: 0.162 AC: 24570 AN: 152088 Hom.: 4592 Cov.: 32 AF XY: 0.160 AC XY: 11920 AN XY: 74348

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.0828

Gnomad4 ASJ AF: 0.0323

Gnomad4 EAS AF: 0.319

Gnomad4 SAS AF: 0.0745

Gnomad4 FIN AF: 0.0535

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.118

Alfa AF: 0.0596 Hom.: 2060

Bravo AF: 0.180

TwinsUK AF: 0.0289 AC: 107

ALSPAC AF: 0.0252 AC: 97

ESP6500AA AF: 0.437 AC: 1927

ESP6500EA AF: 0.0271 AC: 233

ExAC AF: 0.0978 AC: 11879

Asia WGS AF: 0.236 AC: 823 AN: 3478

EpiCase AF: 0.0225

EpiControl AF: 0.0241

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	18
DANN	Benign	0.78
DEOGEN2	Benign	0.0092	T;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.64	T;T
MetaRNN	Benign	0.00076	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	.;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	0.49	N;N
REVEL	Benign	0.072
Sift	Benign	1.0	T;T
Sift4G	Benign	0.69	T;T
Polyphen		0.0	.;B
Vest4		0.045
MPC		0.28
ClinPred		0.0023	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.062
gMVP		0.64

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: rs6643; hg19: chr2-85824251; COSMIC: COSV57817795; COSMIC: COSV57817795;