Genetic Variant RNF181:p.Tyr118His (chr2-85597128-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y118C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 4592 hom., cov: 32)

Exomes 𝑓: 0.050 ( 6725 hom. )

Consequence

RNF181
NM_016494.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.65

Publications

23 publications found

Variant links:

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]

RNF181 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RNF181	NM_016494.4 link	c.352T>C	p.Tyr118His	missense_variant	Exon 4 of 5	ENST00000306368.9	NP_057578.1
RNF181	XM_005264359.5 link	c.393T>C	p.Ala131Ala	synonymous_variant	Exon 3 of 4		XP_005264416.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF181	ENST00000306368.9 link	c.352T>C	p.Tyr118His	missense_variant	Exon 4 of 5	1	NM_016494.4	ENSP00000306906.4

Frequencies

GnomAD3 genomes

AF:

0.161

AC:

24510

AN:

151970

Hom.:

4574

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0900

AC:

22634

AN:

251456

AF XY:

0.0799

show subpopulations

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 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.:

AF XY:

0.0486

AC XY:

35350

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.458

AC:

15345

AN:

33472

American (AMR)

AF:

0.0792

AC:

3543

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0334

AC:

874

AN:

26134

East Asian (EAS)

AF:

0.318

AC:

12619

AN:

39700

South Asian (SAS)

AF:

0.0629

AC:

5425

AN:

86258

European-Finnish (FIN)

AF:

0.0571

AC:

3050

AN:

53416

Middle Eastern (MID)

AF:

0.0452

AC:

261

AN:

5768

European-Non Finnish (NFE)

AF:

0.0249

AC:

27711

AN:

1111992

Other (OTH)

AF:

0.0734

AC:

4432

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

3456

6912

10368

13824

17280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1440

2880

4320

5760

7200

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.162

AC:

24570

AN:

152088

Hom.:

4592

Cov.:

AF XY:

0.160

AC XY:

11920

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.447

AC:

18528

AN:

41434

American (AMR)

AF:

0.0828

AC:

1266

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.0323

AC:

112

AN:

3472

East Asian (EAS)

AF:

0.319

AC:

1643

AN:

5156

South Asian (SAS)

AF:

0.0745

AC:

359

AN:

4818

European-Finnish (FIN)

AF:

0.0535

AC:

566

AN:

10586

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0263

AC:

1791

AN:

68010

Other (OTH)

AF:

0.118

AC:

249

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

782

1563

2345

3126

3908

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

232

464

696

928

1160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0716

Hom.:

5511

Bravo

AF:

0.180

TwinsUK

AF:

0.0289

AC:

107

ALSPAC

AF:

0.0252

AC:

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

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.0092

T;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.64

T;T

MetaRNN

Benign

0.00076

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

.;N

PhyloP100

2.6

PrimateAI

Uncertain

0.60

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

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.062

gMVP

0.64

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over