10-122454932-G-T

Variant names:

• chr10-122454932-G-T
• rs10490924
• NM_001099667.3:c.205G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:4 O:2
• Conservation: PhyloP100: 0.215
• Publications: 722 publications found

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]

ENSG00000285955 (HGNC:58122):

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARMS2	NM_001099667.3	c.205G>T	p.Ala69Ser	missense_variant	Exon 1 of 2	ENST00000528446.1	NP_001093137.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARMS2	ENST00000528446.1	c.205G>T	p.Ala69Ser	missense_variant	Exon 1 of 2	1	NM_001099667.3	ENSP00000436682.1

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35599 AN: 151862 Hom.: 4374 Cov.: 31

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

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.: 36 AF XY: 0.232 AC XY: 168758 AN XY: 726930

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

GnomAD4 genome AF: 0.234 AC: 35639 AN: 151980 Hom.: 4381 Cov.: 31 AF XY: 0.237 AC XY: 17612 AN XY: 74280

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: 59 AN: 292

European-Non Finnish (NFE) AF: 0.219 AC: 14909 AN: 67930

Other (OTH) AF: 0.233 AC: 492 AN: 2112

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

Significance: Benign

Submissions summary: Uncertain:1 Benign:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:1

Oct 17, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17903296, 30389424, 28173125, 16642439, 23274582, 24036949, 20664795, 21203342, 21031019, 22232482, 21825189, 19823576, 19898184, 21397333, 16174643, 20688737, 16936732, 20378180, 20042647, 20381870, 17884985, 20574013, 19933195, 19268887, 21236409, 22893087, 18164066, 23326481, 22509112, 23112567, 21106043) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Department of Ophthalmology and Visual Sciences Kyoto University

Significance: not provided

Review Status: no classification provided

Collection Method: not provided

- -

Age related macular degeneration 8 Benign:1 Other:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Apr 01, 2013

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

ARMS2-related disorder Benign:1

Sep 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.036	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.0061	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.21
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.061
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.038
MPC		1.1
ClinPred		0.045	T
GERP RS		1.0
PromoterAI		-0.0018	Neutral
Varity_R		0.28
gMVP		0.0041
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10490924; hg19: chr10-124214448; COSMIC: COSV73306986;