rs201461814

chr2-9521321-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003183.6(ADAM17):c.844-5T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,566,064 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (68 hom.)
• Consequence: ADAM17 NM_003183.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.6902
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.24

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-9521321-A-G is Benign according to our data. Variant chr2-9521321-A-G is described in ClinVar as [Benign]. Clinvar id is 539951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00601 (915/152250) while in subpopulation NFE AF= 0.00973 (662/68022). AF 95% confidence interval is 0.00912. There are 6 homozygotes in gnomad4. There are 402 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.844-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.844-5T>C		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_003183.6	P1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 914 AN: 152132 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00661 AC: 1659 AN: 250990 Hom.: 8 AF XY: 0.00641 AC XY: 870 AN XY: 135658

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00265

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00835

GnomAD4 exome AF: 0.00868 AC: 12274 AN: 1413814 Hom.: 68 Cov.: 26 AF XY: 0.00848 AC XY: 5988 AN XY: 706054

Gnomad4 AFR exome AF: 0.00161

Gnomad4 AMR exome AF: 0.00392

Gnomad4 ASJ exome AF: 0.00450

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.00569

Gnomad4 NFE exome AF: 0.0103

Gnomad4 OTH exome AF: 0.00676

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152250 Hom.: 6 Cov.: 31 AF XY: 0.00540 AC XY: 402 AN XY: 74442

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00602

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00490

Gnomad4 NFE AF: 0.00973

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00817 Hom.: 1

Bravo AF: 0.00568

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2024

ADAM17: BP4, BS1, BS2 -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	17
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
SpliceAI score (max)		0.030		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: rs201461814; hg19: chr2-9661450;