rs34367192

Positions:

• chr2-9502349-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003183.6(ADAM17):​c.1545-73G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,310,460 control chromosomes in the GnomAD database, including 151,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14253 hom., cov: 31)
  • Exomes 𝑓: 0.47 (136771 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.44

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BP6: Variant 2-9502349-C-T is Benign according to our data. Variant chr2-9502349-C-T is described in ClinVar as [Benign]. Clinvar id is 1188944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.1545-73G>A		intron_variant		ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.1545-73G>A		intron_variant		1	NM_003183.6	ENSP00000309968	P1
	ENST00000472619.2	n.76+808C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63080 AN: 151742 Hom.: 14257 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.468

GnomAD4 exome AF: 0.473 AC: 547772 AN: 1158600 Hom.: 136771 AF XY: 0.472 AC XY: 277357 AN XY: 587216

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.551

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.516

Gnomad4 OTH exome AF: 0.470

GnomAD4 genome AF: 0.416 AC: 63106 AN: 151860 Hom.: 14253 Cov.: 31 AF XY: 0.407 AC XY: 30232 AN XY: 74196

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.549

Gnomad4 EAS AF: 0.0302

Gnomad4 SAS AF: 0.342

Gnomad4 FIN AF: 0.439

Gnomad4 NFE AF: 0.514

Gnomad4 OTH AF: 0.465

Alfa AF: 0.450 Hom.: 2795

Bravo AF: 0.403

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0090
DANN	Benign	0.85

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: rs34367192; hg19: chr2-9642478;