rs2276338

chr2-9505660-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003183.6(ADAM17):c.1345-295G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 375,760 control chromosomes in the GnomAD database, including 54,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (21232 hom., cov: 30)
  • Exomes 𝑓: 0.53 (33315 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.376

Genes affected

ADAM17 (HGNC:195): (ADAM metallopeptidase domain 17) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biologic processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded preproprotein is proteolytically processed to generate the mature protease. The encoded protease functions in the ectodomain shedding of tumor necrosis factor-alpha, in which soluble tumor necrosis factor-alpha is released from the membrane-bound precursor. This protease also functions in the processing of numerous other substrates, including cell adhesion proteins, cytokine and growth factor receptors and epidermal growth factor (EGF) receptor ligands, and plays a prominent role in the activation of the Notch signaling pathway. Elevated expression of this gene has been observed in specific cell types derived from psoriasis, rheumatoid arthritis, multiple sclerosis and Crohn's disease patients, suggesting that the encoded protein may play a role in autoimmune disease. Additionally, this protease may play a role in viral infection through its cleavage of ACE2, the cellular receptor for SARS-CoV and SARS-CoV-2. [provided by RefSeq, Aug 2020]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-9505660-C-T is Benign according to our data. Variant chr2-9505660-C-T is described in ClinVar as [Benign]. Clinvar id is 1245694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.1345-295G>A		intron_variant		ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.1345-295G>A		intron_variant		1	NM_003183.6	P1
	ENST00000472619.2	n.242+50C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78480 AN: 151574 Hom.: 21215 Cov.: 30

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.562

GnomAD4 exome AF: 0.527 AC: 118018 AN: 224068 Hom.: 33315 Cov.: 2 AF XY: 0.521 AC XY: 62373 AN XY: 119636

Gnomad4 AFR exome AF: 0.497

Gnomad4 AMR exome AF: 0.355

Gnomad4 ASJ exome AF: 0.627

Gnomad4 EAS exome AF: 0.0734

Gnomad4 SAS exome AF: 0.449

Gnomad4 FIN exome AF: 0.496

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.518 AC: 78536 AN: 151692 Hom.: 21232 Cov.: 30 AF XY: 0.506 AC XY: 37482 AN XY: 74108

Gnomad4 AFR AF: 0.484

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.0908

Gnomad4 SAS AF: 0.434

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.559

Alfa AF: 0.570 Hom.: 14500

Bravo AF: 0.510

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	0.73
Dann	Benign	0.50

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: rs2276338; hg19: chr2-9645789;