rs1880439

Variant names:

• chr2-9541668-C-A
• rs1880439
• NM_003183.6:c.230+1485G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003183.6(ADAM17):​c.230+1485G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 152,244 control chromosomes in the GnomAD database, including 1,643 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 0.14 (1643 hom., cov: 33)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.295
• Publications: 6 publications found

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]

ADAM17 Gene-Disease associations (from GenCC):

• inflammatory skin and bowel disease, neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.16 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.230+1485G>T		intron_variant	Intron 2 of 18	ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-451+1485G>T		intron_variant	Intron 2 of 18		NP_001369706.1
ADAM17	NM_001382778.1	c.-693+1485G>T		intron_variant	Intron 2 of 18		NP_001369707.1
ADAM17	XM_047445610.1	c.137+1485G>T		intron_variant	Intron 3 of 19		XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.230+1485G>T		intron_variant	Intron 2 of 18	1	NM_003183.6	ENSP00000309968.3
ADAM17	ENST00000618923.2	n.230+1485G>T		intron_variant	Intron 2 of 7	1		ENSP00000480552.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 21732 AN: 152126 Hom.: 1641 Cov.: 33

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.141

Gnomad EAS AF: 0.0610

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.0913

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.138

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.143 AC: 21742 AN: 152244 Hom.: 1643 Cov.: 33 AF XY: 0.138 AC XY: 10285 AN XY: 74434

African (AFR) AF: 0.150 AC: 6240 AN: 41532

American (AMR) AF: 0.110 AC: 1690 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.141 AC: 488 AN: 3468

East Asian (EAS) AF: 0.0607 AC: 315 AN: 5186

South Asian (SAS) AF: 0.106 AC: 510 AN: 4832

European-Finnish (FIN) AF: 0.0913 AC: 969 AN: 10608

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 11047 AN: 68000

Other (OTH) AF: 0.137 AC: 290 AN: 2116

Alfa AF: 0.155 Hom.: 2472

Bravo AF: 0.144

Asia WGS AF: 0.0920 AC: 321 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.81
DANN	Benign	0.38
PhyloP100		-0.29
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1880439; hg19: chr2-9681797;