rs1056204

chr2-9506962-A-Cchr2-9506962-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003183.6(ADAM17):c.1345-1597T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 151,950 control chromosomes in the GnomAD database, including 4,761 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.23 (4760 hom., cov: 31)
  • Exomes 𝑓: 0.31 (1 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.257

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.306 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.1345-1597T>G		intron_variant		ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.1345-1597T>G		intron_variant		1	NM_003183.6	P1
	ENST00000472619.2	n.242+1352A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34880 AN: 151816 Hom.: 4764 Cov.: 31

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.00503

Gnomad SAS AF: 0.249

Gnomad FIN AF: 0.286

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.313 AC: 5 AN: 16 Hom.: 1 Cov.: 0 AF XY: 0.357 AC XY: 5 AN XY: 14

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.417

GnomAD4 genome AF: 0.230 AC: 34879 AN: 151934 Hom.: 4760 Cov.: 31 AF XY: 0.226 AC XY: 16766 AN XY: 74278

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.00504

Gnomad4 SAS AF: 0.248

Gnomad4 FIN AF: 0.286

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.266

Alfa AF: 0.291 Hom.: 13416

Bravo AF: 0.213

Asia WGS AF: 0.112 AC: 388 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	4.7
Dann	Benign	0.68

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: rs1056204; hg19: chr2-9647091;