10-122454735-G-A

Position:

• chr10-122454735-G-A

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.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. 14/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.560

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:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARMS2	NM_001099667.3	c.8G>A	p.Arg3His	missense_variant	1/2	ENST00000528446.1	NP_001093137.1
LOC105378525	XR_946382.3	n.1874+3760C>T		intron_variant
LOC105378525	XR_946383.3	n.1852+3760C>T		intron_variant
LOC105378525	XR_946384.3	n.1601+3760C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMS2	ENST00000528446.1	c.8G>A	p.Arg3His	missense_variant	1/2	1	NM_001099667.3	ENSP00000436682.1
ENSG00000285955	ENST00000647969.1	n.182+3760C>T		intron_variant
ENSG00000285955	ENST00000650300.1	n.1852+3760C>T		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0931 AC: 14152 AN: 152014 Hom.: 857 Cov.: 31

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

GnomAD3 exomes AF: 0.105 AC: 26213 AN: 249074 Hom.: 1703 AF XY: 0.110 AC XY: 14923 AN XY: 135126

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 SAS exome AF: 0.143

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.: 32 AF XY: 0.120 AC XY: 87176 AN XY: 727008

Gnomad4 AFR exome AF: 0.0343

Gnomad4 AMR exome AF: 0.0687

Gnomad4 ASJ exome AF: 0.176

Gnomad4 EAS exome AF: 0.00456

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0862

Gnomad4 NFE exome AF: 0.125

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.0930 AC: 14147 AN: 152132 Hom.: 856 Cov.: 31 AF XY: 0.0913 AC XY: 6788 AN XY: 74368

Gnomad4 AFR AF: 0.0363

Gnomad4 AMR AF: 0.0948

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.00677

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0745

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.110

Alfa AF: 0.116 Hom.: 2006

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Age related macular degeneration 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.20
DANN	Benign	0.25
DEOGEN2	Benign	0.0017	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.000070	N
LIST_S2	Benign	0.30	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.021
Sift	Benign	0.52	T
Sift4G	Benign	0.92	T
Polyphen		0.0	B
Vest4		0.012
MPC		0.57
ClinPred		0.000057	T
GERP RS		-0.73
Varity_R		0.023
gMVP		0.0056

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: rs10490923; hg19: chr10-124214251; COSMIC: COSV73306987;