10-122456894-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001099667.3(ARMS2):c.298-13A>T 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 0.00299 in 1,510,222 control chromosomes in the GnomAD database, including 91 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (29 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (62 hom.)
• Consequence: ARMS2 NM_001099667.3 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-122456894-A-T is Benign according to our data. Variant chr10-122456894-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 299032.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0119 (1804/151196) while in subpopulation AFR AF= 0.04 (1647/41158). AF 95% confidence interval is 0.0384. There are 29 homozygotes in gnomad4. There are 850 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 29 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARMS2	NM_001099667.3	c.298-13A>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000528446.1
LOC105378525	XR_946382.3	n.1874+1601T>A		intron_variant, non_coding_transcript_variant

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1798 AN: 151076 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00582

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00753

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000207

Gnomad OTH AF: 0.00824

GnomAD3 exomes AF: 0.00386 AC: 538 AN: 139318 Hom.: 11 AF XY: 0.00398 AC XY: 294 AN XY: 73790

Gnomad AFR exome AF: 0.0401

Gnomad AMR exome AF: 0.00215

Gnomad ASJ exome AF: 0.000126

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00822

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000355

Gnomad OTH exome AF: 0.00126

GnomAD4 exome AF: 0.00199 AC: 2708 AN: 1359026 Hom.: 62 Cov.: 33 AF XY: 0.00211 AC XY: 1417 AN XY: 670354

Gnomad4 AFR exome AF: 0.0456

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.0000821

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00866

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000290

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.0119 AC: 1804 AN: 151196 Hom.: 29 Cov.: 32 AF XY: 0.0115 AC XY: 850 AN XY: 73798

Gnomad4 AFR AF: 0.0400

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00753

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.00815

Alfa AF: 0.000312 Hom.: 303

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Age related macular degeneration 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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	-0.89
Cadd	Benign	0.68
Dann	Benign	0.70

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;