dbSNP rs10490923: ARMS2:p.Arg3His (chr10-122454735-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001099667.3(ARMS2):c.8G>A(p.Arg3His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 1,613,550 control chromosomes in the GnomAD database, including 11,935 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 856 hom., cov: 31)

Exomes 𝑓: 0.12 ( 11079 hom. )

Consequence

ARMS2
NM_001099667.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.560

Publications

42 publications found

Variant links:

Genes affected

ARMS2 (HGNC:32685): (age-related maculopathy susceptibility 2) This gene encodes a small secreted protein specific to primates. This protein is a component of the choroidal extracellular matrix of the eye. Mutations in this gene are associated with age-related macular degeneration. [provided by RefSeq, Sep 2017]

ARMS2 links:

HTRA1-AS1 (HGNC:58122):

HTRA1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0013993382).

BP6

Variant 10-122454735-G-A is Benign according to our data. Variant chr10-122454735-G-A is described in ClinVar as Benign. ClinVar VariationId is 299028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001099667.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARMS2	NM_001099667.3	MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 2	NP_001093137.1	P0C7Q2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ARMS2	ENST00000528446.1	TSL:1 MANE Select	c.8G>A	p.Arg3His	missense	Exon 1 of 2	ENSP00000436682.1	P0C7Q2
HTRA1-AS1	ENST00000647969.1		n.182+3760C>T		intron	N/A
HTRA1-AS1	ENST00000650300.1		n.1852+3760C>T		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0931

AC:

14152

AN:

152014

Hom.:

857

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0364

Gnomad AMI

AF:

0.173

Gnomad AMR

AF:

0.0950

Gnomad ASJ

AF:

0.181

Gnomad EAS

AF:

0.00656

Gnomad SAS

AF:

0.150

Gnomad FIN

AF:

0.0745

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.126

Gnomad OTH

AF:

0.111

GnomAD2 exomes

AF:

0.105

AC:

26213

AN:

249074

AF XY:

0.110

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.0643

Gnomad ASJ exome

AF:

0.178

Gnomad EAS exome

AF:

0.00801

Gnomad FIN exome

AF:

0.0832

Gnomad NFE exome

AF:

0.129

Gnomad OTH exome

AF:

0.126

GnomAD4 exome

AF:

0.119

AC:

173203

AN:

1461418

Hom.:

11079

Cov.:

AF XY:

0.120

AC XY:

87176

AN XY:

727008

show subpopulations

African (AFR)

AF:

0.0343

AC:

1147

AN:

33478

American (AMR)

AF:

0.0687

AC:

3071

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

4590

AN:

26128

East Asian (EAS)

AF:

0.00456

AC:

181

AN:

39700

South Asian (SAS)

AF:

0.143

AC:

12348

AN:

86242

European-Finnish (FIN)

AF:

0.0862

AC:

4603

AN:

53394

Middle Eastern (MID)

AF:

0.179

AC:

1010

AN:

5658

European-Non Finnish (NFE)

AF:

0.125

AC:

139357

AN:

1111744

Other (OTH)

AF:

0.114

AC:

6896

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

8015

16030

24046

32061

40076

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4942

9884

14826

19768

24710

<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:

0.0930

AC:

14147

AN:

152132

Hom.:

856

Cov.:

AF XY:

0.0913

AC XY:

6788

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.0363

AC:

1509

AN:

41518

American (AMR)

AF:

0.0948

AC:

1449

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.181

AC:

629

AN:

3470

East Asian (EAS)

AF:

0.00677

AC:

AN:

5168

South Asian (SAS)

AF:

0.149

AC:

718

AN:

4810

European-Finnish (FIN)

AF:

0.0745

AC:

789

AN:

10596

Middle Eastern (MID)

AF:

0.211

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.126

AC:

8567

AN:

67980

Other (OTH)

AF:

0.110

AC:

232

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

640

1280

1920

2560

3200

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

162

324

486

648

810

<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:

0.112

Hom.:

2708

Bravo

AF:

0.0880

TwinsUK

AF:

0.130

AC:

481

ALSPAC

AF:

0.118

AC:

455

ESP6500AA

AF:

0.0357

AC:

148

ESP6500EA

AF:

0.130

AC:

1091

ExAC

AF:

0.106

AC:

12880

Asia WGS

AF:

0.0820

AC:

284

AN:

3478

EpiCase

AF:

0.137

EpiControl

AF:

0.141

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Age related macular degeneration 8 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.058

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.81

CADD

Benign

0.20

(source)

DANN

Benign

0.25

DEOGEN2

Benign

0.0017

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.000070

LIST_S2

Benign

0.30

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.56

PrimateAI

Benign

0.29

PROVEAN

Benign

2.1

REVEL

Benign

0.021

Sift

Benign

0.52

Sift4G

Benign

0.92

Polyphen

0.0

Vest4

0.012

MPC

0.57

ClinPred

0.000057

GERP RS

-0.73

PromoterAI

-0.0098

Neutral

(source)

Varity_R

0.023

gMVP

0.0056

Mutation Taster

=99/1

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over