rs4752698

Positions:

• chr10-122457306-T-G

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.*373T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 203,018 control chromosomes in the GnomAD database, including 1,805 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1215 hom., cov: 31)
  • Exomes 𝑓: 0.12 (590 hom.)
• Consequence: ARMS2 NM_001099667.3 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0280

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 (BayesDel_noAF=-0.9).
• BP6: Variant 10-122457306-T-G is Benign according to our data. Variant chr10-122457306-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 299038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ARMS2	NM_001099667.3	c.*373T>G		3_prime_UTR_variant	2/2	ENST00000528446.1	NP_001093137.1
LOC105378525	XR_946382.3	n.1874+1189A>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMS2	ENST00000528446.1	c.*373T>G		3_prime_UTR_variant	2/2	1	NM_001099667.3	ENSP00000436682	P1
	ENST00000650300.1	n.1852+1189A>C		intron_variant, non_coding_transcript_variant
	ENST00000647969.1	n.182+1189A>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.101 AC: 14210 AN: 141340 Hom.: 1217 Cov.: 31

Gnomad AFR AF: 0.0393

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.192

Gnomad EAS AF: 0.00841

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.213

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.123

GnomAD4 exome AF: 0.124 AC: 7648 AN: 61576 Hom.: 590 Cov.: 0 AF XY: 0.127 AC XY: 3934 AN XY: 30906

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.0856

Gnomad4 ASJ exome AF: 0.175

Gnomad4 EAS exome AF: 0.00293

Gnomad4 SAS exome AF: 0.194

Gnomad4 FIN exome AF: 0.0911

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.128

GnomAD4 genome AF: 0.100 AC: 14205 AN: 141442 Hom.: 1215 Cov.: 31 AF XY: 0.0981 AC XY: 6773 AN XY: 69026

Gnomad4 AFR AF: 0.0393

Gnomad4 AMR AF: 0.101

Gnomad4 ASJ AF: 0.192

Gnomad4 EAS AF: 0.00867

Gnomad4 SAS AF: 0.171

Gnomad4 FIN AF: 0.0763

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.121

Alfa AF: 0.126 Hom.: 346

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

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

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Macular degeneration Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.2
DANN	Benign	0.49

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: rs4752698; hg19: chr10-124216822;