rs10495563

Positions:

• chr2-9522081-G-A
• chr2-9522081-G-C
• chr2-9522081-G-T

Variant summary

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

The ENST00000310823.8(ADAM17):​c.844-765C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 225,584 control chromosomes in the GnomAD database, including 47,211 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 (31965 hom., cov: 33)
  • Exomes 𝑓: 0.62 (15246 hom.)
• Consequence: ADAM17 ENST00000310823.8 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728

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=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.844-765C>T		intron_variant		ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.844-765C>T		intron_variant		1	NM_003183.6	ENSP00000309968	P1

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96272 AN: 151956 Hom.: 31935 Cov.: 33

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.618 AC: 45406 AN: 73512 Hom.: 15246 Cov.: 0 AF XY: 0.622 AC XY: 22748 AN XY: 36568

Gnomad4 AFR exome AF: 0.740

Gnomad4 AMR exome AF: 0.430

Gnomad4 ASJ exome AF: 0.694

Gnomad4 EAS exome AF: 0.0480

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.576

Gnomad4 NFE exome AF: 0.688

Gnomad4 OTH exome AF: 0.629

GnomAD4 genome AF: 0.634 AC: 96345 AN: 152072 Hom.: 31965 Cov.: 33 AF XY: 0.618 AC XY: 45958 AN XY: 74334

Gnomad4 AFR AF: 0.717

Gnomad4 AMR AF: 0.490

Gnomad4 ASJ AF: 0.690

Gnomad4 EAS AF: 0.0912

Gnomad4 SAS AF: 0.448

Gnomad4 FIN AF: 0.532

Gnomad4 NFE AF: 0.678

Gnomad4 OTH AF: 0.653

Alfa AF: 0.648 Hom.: 62893

Bravo AF: 0.631

Asia WGS AF: 0.313 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.5
DANN	Benign	0.45

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: rs10495563; hg19: chr2-9662210;