2-9490115-ATT-AT

Variant names:

• chr2-9490115-AT-A
• rs3833563
• NM_003183.6:c.*61delA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003183.6(ADAM17):​c.*61delA 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
• Publications: 5 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]

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

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.*61delA		3_prime_UTR	Exon 19 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.*61delA		3_prime_UTR	Exon 19 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.*61delA		3_prime_UTR	Exon 19 of 19	NP_001369707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.*61delA		3_prime_UTR	Exon 19 of 19	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000926352.1		c.*61delA		3_prime_UTR	Exon 20 of 20	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.*61delA		3_prime_UTR	Exon 19 of 19	ENSP00000615343.1

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

African (AFR) AF: 0.487 AC: 14061 AN: 28860

American (AMR) AF: 0.308 AC: 9684 AN: 31486

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 12827 AN: 20372

East Asian (EAS) AF: 0.0624 AC: 2367 AN: 37936

South Asian (SAS) AF: 0.456 AC: 31843 AN: 69822

European-Finnish (FIN) AF: 0.488 AC: 23396 AN: 47948

Middle Eastern (MID) AF: 0.647 AC: 2474 AN: 3824

European-Non Finnish (NFE) AF: 0.594 AC: 581108 AN: 978700

Other (OTH) AF: 0.552 AC: 29260 AN: 52966

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

African (AFR) AF: 0.482 AC: 19956 AN: 41388

American (AMR) AF: 0.415 AC: 6291 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2174 AN: 3462

East Asian (EAS) AF: 0.0908 AC: 471 AN: 5186

South Asian (SAS) AF: 0.435 AC: 2099 AN: 4822

European-Finnish (FIN) AF: 0.465 AC: 4914 AN: 10558

Middle Eastern (MID) AF: 0.671 AC: 196 AN: 292

European-Non Finnish (NFE) AF: 0.593 AC: 40110 AN: 67662

Other (OTH) AF: 0.556 AC: 1171 AN: 2108

Alfa AF: 0.554 Hom.: 2195

Bravo AF: 0.506

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inflammatory skin and bowel disease, neonatal, 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
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: rs3833563; hg19: chr2-9630244; COSMIC: COSV60397356; COSMIC: COSV60397356;