2-9546311-A-G

Variant names:

• chr2-9546311-A-G
• rs10495565
• NM_003183.6:c.98-3026T>C

Variant summary

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

The ENST00000310823.8(ADAM17):​c.98-3026T>C 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 152,088 control chromosomes in the GnomAD database, including 4,791 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 (4791 hom., cov: 32)
• Consequence: ADAM17 ENST00000310823.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 9 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.307 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000310823.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.98-3026T>C		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.-583-3026T>C		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.-825-3026T>C		intron	N/A	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.98-3026T>C		intron	N/A	ENSP00000309968.3
	ADAM17	ENST00000478059.1	TSL:1	n.267-3026T>C		intron	N/A
	ADAM17	ENST00000618923.2	TSL:1	n.98-3026T>C		intron	N/A	ENSP00000480552.1

Frequencies

GnomAD3 genomes AF: 0.230 AC: 34945 AN: 151970 Hom.: 4796 Cov.: 32

Gnomad AFR AF: 0.111

Gnomad AMI AF: 0.289

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.312

Gnomad EAS AF: 0.00499

Gnomad SAS AF: 0.248

Gnomad FIN AF: 0.288

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.268

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

GnomAD4 genome AF: 0.230 AC: 34942 AN: 152088 Hom.: 4791 Cov.: 32 AF XY: 0.226 AC XY: 16790 AN XY: 74346

African (AFR) AF: 0.111 AC: 4592 AN: 41498

American (AMR) AF: 0.197 AC: 3009 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 1083 AN: 3468

East Asian (EAS) AF: 0.00501 AC: 26 AN: 5194

South Asian (SAS) AF: 0.247 AC: 1190 AN: 4820

European-Finnish (FIN) AF: 0.288 AC: 3041 AN: 10574

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21078 AN: 67960

Other (OTH) AF: 0.267 AC: 564 AN: 2110

Alfa AF: 0.150 Hom.: 335

Bravo AF: 0.213

Asia WGS AF: 0.110 AC: 380 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.75
PhyloP100		1.3
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: rs10495565; hg19: chr2-9686440;