10-122454839-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4 BP6_Very_Strong BA1

The NM_001099667.3(ARMS2):c.112C>T(p.Arg38Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,820 control chromosomes in the GnomAD database, including 18,056 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.13 (1497 hom., cov: 31)
  • Exomes 𝑓: 0.15 (16559 hom.)
• Consequence: ARMS2 NM_001099667.3 stop_gained
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.417

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 -14 ACMG points.

• PM4: Stoplost variant in NM_001099667.3 Downstream stopcodon found after 132 codons.
• BP6: Variant 10-122454839-C-T is Benign according to our data. Variant chr10-122454839-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 299029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMS2	NM_001099667.3	c.112C>T	p.Arg38Ter	stop_gained	1/2	ENST00000528446.1
LOC105378525	XR_946382.3	n.1874+3656G>A		intron_variant, non_coding_transcript_variant
LOC105378525	XR_946383.3	n.1852+3656G>A		intron_variant, non_coding_transcript_variant
LOC105378525	XR_946384.3	n.1601+3656G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARMS2	ENST00000528446.1	c.112C>T	p.Arg38Ter	stop_gained	1/2	1	NM_001099667.3	P1
	ENST00000650300.1	n.1852+3656G>A		intron_variant, non_coding_transcript_variant
	ENST00000647969.1	n.182+3656G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19959 AN: 152014 Hom.: 1494 Cov.: 31

Gnomad AFR AF: 0.0749

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.166

Gnomad SAS AF: 0.0682

Gnomad FIN AF: 0.171

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.137

GnomAD3 exomes AF: 0.131 AC: 32700 AN: 249226 Hom.: 2409 AF XY: 0.130 AC XY: 17629 AN XY: 135210

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.155

Gnomad SAS exome AF: 0.0689

Gnomad FIN exome AF: 0.162

Gnomad NFE exome AF: 0.154

Gnomad OTH exome AF: 0.133

GnomAD4 exome AF: 0.146 AC: 213900 AN: 1461688 Hom.: 16559 Cov.: 34 AF XY: 0.144 AC XY: 104970 AN XY: 727124

Gnomad4 AFR exome AF: 0.0705

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.130

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.0690

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.155

Gnomad4 OTH exome AF: 0.137

GnomAD4 genome AF: 0.131 AC: 19976 AN: 152132 Hom.: 1497 Cov.: 31 AF XY: 0.130 AC XY: 9658 AN XY: 74376

Gnomad4 AFR AF: 0.0753

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.136

Gnomad4 EAS AF: 0.165

Gnomad4 SAS AF: 0.0680

Gnomad4 FIN AF: 0.171

Gnomad4 NFE AF: 0.161

Gnomad4 OTH AF: 0.136

Alfa AF: 0.134 Hom.: 1253

Bravo AF: 0.125

TwinsUK AF: 0.150 AC: 557

ALSPAC AF: 0.158 AC: 608

ESP6500AA AF: 0.0709 AC: 288

ESP6500EA AF: 0.152 AC: 1274

ExAC AF: 0.131 AC: 15813

Asia WGS AF: 0.106 AC: 369 AN: 3478

EpiCase AF: 0.151

EpiControl AF: 0.147

ClinVar

Significance: Benign/Likely 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

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. -

ARMS2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as likely 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
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Benign	0.95
Eigen	Benign	-0.63
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.0040	N
MutationTaster	Benign	0.000089	P
Vest4		0.66
GERP RS		-2.2

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: rs2736911; hg19: chr10-124214355; COSMIC: COSV73306995;