rs6432017

Variant names:

• chr2-9553746-G-A
• rs6432017
• NM_003183.6:c.97+1763C>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.97+1763C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.635 in 151,390 control chromosomes in the GnomAD database, including 31,913 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 0.63 (31913 hom., cov: 29)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.133
• Publications: 14 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.97+1763C>T		intron_variant	Intron 1 of 18	ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-584+1763C>T		intron_variant	Intron 1 of 18		NP_001369706.1
ADAM17	NM_001382778.1	c.-826+1763C>T		intron_variant	Intron 1 of 18		NP_001369707.1
ADAM17	XM_047445610.1	c.-62+1763C>T		intron_variant	Intron 1 of 19		XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.97+1763C>T		intron_variant	Intron 1 of 18	1	NM_003183.6	ENSP00000309968.3
ADAM17	ENST00000618923.2	n.97+1763C>T		intron_variant	Intron 1 of 7	1		ENSP00000480552.1

Frequencies

GnomAD3 genomes AF: 0.635 AC: 95994 AN: 151274 Hom.: 31882 Cov.: 29

Gnomad AFR AF: 0.719

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.495

Gnomad ASJ AF: 0.688

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.452

Gnomad FIN AF: 0.529

Gnomad MID AF: 0.755

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.660

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

GnomAD4 genome AF: 0.635 AC: 96069 AN: 151390 Hom.: 31913 Cov.: 29 AF XY: 0.620 AC XY: 45812 AN XY: 73946

African (AFR) AF: 0.719 AC: 29649 AN: 41216

American (AMR) AF: 0.494 AC: 7511 AN: 15200

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 2389 AN: 3470

East Asian (EAS) AF: 0.0916 AC: 469 AN: 5122

South Asian (SAS) AF: 0.451 AC: 2171 AN: 4810

European-Finnish (FIN) AF: 0.529 AC: 5494 AN: 10378

Middle Eastern (MID) AF: 0.757 AC: 221 AN: 292

European-Non Finnish (NFE) AF: 0.678 AC: 46013 AN: 67892

Other (OTH) AF: 0.656 AC: 1376 AN: 2098

Alfa AF: 0.660 Hom.: 17140

Bravo AF: 0.633

Asia WGS AF: 0.317 AC: 1105 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.99
DANN	Benign	0.43
PhyloP100		0.13
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: rs6432017; hg19: chr2-9693875;