rs7088128

Positions:

• chr10-122456894-A-G
• chr10-122456894-A-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.298-13A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.12 in 1,507,780 control chromosomes in the GnomAD database, including 10,778 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 (922 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9856 hom.)
• Consequence: ARMS2 NM_001099667.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.213

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 10-122456894-A-G is Benign according to our data. Variant chr10-122456894-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 299031.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.298-13A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000528446.1	NP_001093137.1
LOC105378525	XR_946382.3	n.1874+1601T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ARMS2	ENST00000528446.1	c.298-13A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001099667.3	ENSP00000436682	P1
	ENST00000650300.1	n.1852+1601T>C		intron_variant, non_coding_transcript_variant
	ENST00000647969.1	n.182+1601T>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15534 AN: 151044 Hom.: 924 Cov.: 32

Gnomad AFR AF: 0.0696

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.0997

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.00658

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.126

Gnomad OTH AF: 0.119

GnomAD3 exomes AF: 0.116 AC: 16199 AN: 139318 Hom.: 1010 AF XY: 0.121 AC XY: 8908 AN XY: 73790

Gnomad AFR exome AF: 0.0739

Gnomad AMR exome AF: 0.0803

Gnomad ASJ exome AF: 0.187

Gnomad EAS exome AF: 0.00831

Gnomad SAS exome AF: 0.155

Gnomad FIN exome AF: 0.0838

Gnomad NFE exome AF: 0.138

Gnomad OTH exome AF: 0.139

GnomAD4 exome AF: 0.122 AC: 164861 AN: 1356616 Hom.: 9856 Cov.: 33 AF XY: 0.123 AC XY: 82084 AN XY: 669312

Gnomad4 AFR exome AF: 0.0692

Gnomad4 AMR exome AF: 0.0780

Gnomad4 ASJ exome AF: 0.178

Gnomad4 EAS exome AF: 0.00429

Gnomad4 SAS exome AF: 0.147

Gnomad4 FIN exome AF: 0.0870

Gnomad4 NFE exome AF: 0.126

Gnomad4 OTH exome AF: 0.119

GnomAD4 genome AF: 0.103 AC: 15532 AN: 151164 Hom.: 922 Cov.: 32 AF XY: 0.100 AC XY: 7381 AN XY: 73770

Gnomad4 AFR AF: 0.0696

Gnomad4 AMR AF: 0.0995

Gnomad4 ASJ AF: 0.182

Gnomad4 EAS AF: 0.00679

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0730

Gnomad4 NFE AF: 0.126

Gnomad4 OTH AF: 0.118

Alfa AF: 0.0968 Hom.: 303

Bravo AF: 0.113

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

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

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	0.85
DANN	Benign	0.63

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: rs7088128; hg19: chr10-124216410;