2-9490115-AT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003183.6(ADAM17):c.*61del variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20928 hom., cov: 0)
  • Exomes 𝑓: 0.56 (203790 hom.)
• Consequence: ADAM17 NM_003183.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.00

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]

IAH1 (HGNC:27696): (isoamyl acetate hydrolyzing esterase 1 (putative)) Enables identical protein binding activity. Predicted to be involved in lipid catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-9490115-AT-A is Benign according to our data. Variant chr2-9490115-AT-A is described in ClinVar as [Benign]. Clinvar id is 1188896.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.*61del		3_prime_UTR_variant	19/19	ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.*61del		3_prime_UTR_variant	19/19	1	NM_003183.6	P1

Frequencies

GnomAD3 genomes AF: 0.515 AC: 77991 AN: 151428 Hom.: 20911 Cov.: 0

Gnomad AFR AF: 0.482

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.416

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.669

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.559

GnomAD4 exome AF: 0.556 AC: 707020 AN: 1271914 Hom.: 203790 Cov.: 0 AF XY: 0.555 AC XY: 346864 AN XY: 624660

Gnomad4 AFR exome AF: 0.487

Gnomad4 AMR exome AF: 0.308

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.0624

Gnomad4 SAS exome AF: 0.456

Gnomad4 FIN exome AF: 0.488

Gnomad4 NFE exome AF: 0.594

Gnomad4 OTH exome AF: 0.552

GnomAD4 genome AF: 0.515 AC: 78045 AN: 151544 Hom.: 20928 Cov.: 0 AF XY: 0.503 AC XY: 37286 AN XY: 74104

Gnomad4 AFR AF: 0.482

Gnomad4 AMR AF: 0.415

Gnomad4 ASJ AF: 0.628

Gnomad4 EAS AF: 0.0908

Gnomad4 SAS AF: 0.435

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.556

Alfa AF: 0.554 Hom.: 2195

Bravo AF: 0.506

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

This variant is classified as Benign based on local population frequency. This variant was detected in 56% of patients studied by a panel of primary immunodeficiencies. Number of patients: 54. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Inflammatory skin and bowel disease, neonatal, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs3833563; hg19: chr2-9630244;