2-9546311-A-G

Position:

• chr2-9546311-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.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 NM_003183.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.98-3026T>C		intron_variant		ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-583-3026T>C		intron_variant			NP_001369706.1
ADAM17	NM_001382778.1	c.-825-3026T>C		intron_variant			NP_001369707.1
ADAM17	XM_047445610.1	c.-61-2551T>C		intron_variant			XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.98-3026T>C		intron_variant		1	NM_003183.6	ENSP00000309968	P1

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

Gnomad4 AFR AF: 0.111

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.312

Gnomad4 EAS AF: 0.00501

Gnomad4 SAS AF: 0.247

Gnomad4 FIN AF: 0.288

Gnomad4 NFE AF: 0.310

Gnomad4 OTH AF: 0.267

Alfa AF: 0.150 Hom.: 320

Bravo AF: 0.213

Asia WGS AF: 0.110 AC: 380 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	8.7
DANN	Benign	0.75

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: rs10495565; hg19: chr2-9686440;