10-122454932-G-T

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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:3 O:2
• Conservation: PhyloP100: 0.215

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
ARMS2	NM_001099667.3	c.205G>T	p.Ala69Ser	missense_variant	1/2	ENST00000528446.1
LOC105378525	XR_946382.3	n.1874+3563C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMS2	ENST00000528446.1	c.205G>T	p.Ala69Ser	missense_variant	1/2	1	NM_001099667.3	P1
	ENST00000650300.1	n.1852+3563C>A		intron_variant, non_coding_transcript_variant
	ENST00000647969.1	n.182+3563C>A		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.255 AC: 63112 AN: 247210 Hom.: 8554 AF XY: 0.255 AC XY: 34187 AN XY: 134312

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 SAS exome AF: 0.318

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

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.205

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.216

Gnomad4 OTH exome AF: 0.241

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

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.233

Gnomad4 ASJ AF: 0.203

Gnomad4 EAS AF: 0.415

Gnomad4 SAS AF: 0.318

Gnomad4 FIN AF: 0.235

Gnomad4 NFE AF: 0.219

Gnomad4 OTH AF: 0.233

Alfa AF: 0.244 Hom.: 10509

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:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:1 Other:1

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 17, 2019	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) -
not provided, no classification provided	not provided	Department of Ophthalmology and Visual Sciences Kyoto University	-	- -

Age related macular degeneration 8 Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
risk factor, no assertion criteria provided	literature only	OMIM	Apr 01, 2013	- -

ARMS2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2019

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
MutationTaster	Benign	1.0	P
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
Varity_R		0.28
gMVP		0.0041

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