Genetic Variant ARMS2:p.Ala69Ser (chr10-122454932-G-T) – 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.205G>T(p.Ala69Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,613,268 control chromosomes in the GnomAD database, including 44,676 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4381 hom., cov: 31)

Exomes 𝑓: 0.23 ( 40295 hom. )

Consequence

ARMS2
NM_001099667.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:4O:2

Conservation

PhyloP100: 0.215

Publications

722 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=0.0016501844).

BP6

Variant 10-122454932-G-T is Benign according to our data. Variant chr10-122454932-G-T is described in ClinVar as Benign. ClinVar VariationId is 979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.4 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.205G>T	p.Ala69Ser	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.205G>T	p.Ala69Ser	missense	Exon 1 of 2	ENSP00000436682.1	P0C7Q2
HTRA1-AS1	ENST00000647969.1		n.182+3563C>A		intron	N/A
HTRA1-AS1	ENST00000650300.1		n.1852+3563C>A		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

35599

AN:

151862

Hom.:

4374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.289

Gnomad AMR

AF:

0.232

Gnomad ASJ

AF:

0.203

Gnomad EAS

AF:

0.414

Gnomad SAS

AF:

0.317

Gnomad FIN

AF:

0.235

Gnomad MID

AF:

0.191

Gnomad NFE

AF:

0.219

Gnomad OTH

AF:

0.236

GnomAD2 exomes

AF:

0.255

AC:

63112

AN:

247210

AF XY:

0.255

show subpopulations

Gnomad AFR exome

AF:

0.233

Gnomad AMR exome

AF:

0.269

Gnomad ASJ exome

AF:

0.215

Gnomad EAS exome

AF:

0.424

Gnomad FIN exome

AF:

0.233

Gnomad NFE exome

AF:

0.218

Gnomad OTH exome

AF:

0.252

GnomAD4 exome

AF:

0.230

AC:

336596

AN:

1461288

Hom.:

40295

Cov.:

AF XY:

0.232

AC XY:

168758

AN XY:

726930

show subpopulations

African (AFR)

AF:

0.233

AC:

7807

AN:

33476

American (AMR)

AF:

0.268

AC:

12004

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.205

AC:

5357

AN:

26134

East Asian (EAS)

AF:

0.384

AC:

15250

AN:

39696

South Asian (SAS)

AF:

0.320

AC:

27604

AN:

86252

European-Finnish (FIN)

AF:

0.239

AC:

12743

AN:

53384

Middle Eastern (MID)

AF:

0.207

AC:

1193

AN:

5766

European-Non Finnish (NFE)

AF:

0.216

AC:

240061

AN:

1111504

Other (OTH)

AF:

0.241

AC:

14577

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

13960

27921

41881

55842

69802

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8502

17004

25506

34008

42510

<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:

0.234

AC:

35639

AN:

151980

Hom.:

4381

Cov.:

AF XY:

0.237

AC XY:

17612

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.229

AC:

9506

AN:

41456

American (AMR)

AF:

0.233

AC:

3556

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.203

AC:

704

AN:

3468

East Asian (EAS)

AF:

0.415

AC:

2134

AN:

5144

South Asian (SAS)

AF:

0.318

AC:

1526

AN:

4798

European-Finnish (FIN)

AF:

0.235

AC:

2489

AN:

10580

Middle Eastern (MID)

AF:

0.202

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.219

AC:

14909

AN:

67930

Other (OTH)

AF:

0.233

AC:

492

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1347

2694

4040

5387

6734

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.235

Hom.:

20218

Bravo

AF:

0.236

TwinsUK

AF:

0.224

AC:

829

ALSPAC

AF:

0.220

AC:

847

ESP6500AA

AF:

0.205

AC:

824

ESP6500EA

AF:

0.206

AC:

1724

ExAC

AF:

0.255

AC:

30770

Asia WGS

AF:

0.369

AC:

1278

AN:

3478

EpiCase

AF:

0.217

EpiControl

AF:

0.212

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Age related macular degeneration 8 (2)

ARMS2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.036

Eigen

Benign

-0.50

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.0061

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.21

PrimateAI

Benign

0.28

PROVEAN

Uncertain

-2.6

REVEL

Benign

0.061

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.99

Vest4

0.038

MPC

1.1

ClinPred

0.045

GERP RS

1.0

PromoterAI

-0.0018

Neutral

(source)

Varity_R

0.28

gMVP

0.0041

Mutation Taster

=100/0

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