rs4622692

chr2-9493008-T-G

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.1994-22A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,583,820 control chromosomes in the GnomAD database, including 265,421 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27130 hom., cov: 33)
  • Exomes 𝑓: 0.57 (238291 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.39

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 2-9493008-T-G is Benign according to our data. Variant chr2-9493008-T-G is described in ClinVar as [Benign]. Clinvar id is 1188898.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.1994-22A>C		intron_variant		ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.1994-22A>C		intron_variant		1	NM_003183.6	P1

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88487 AN: 152004 Hom.: 27099 Cov.: 33

Gnomad AFR AF: 0.707

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.446

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.0918

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.467

Gnomad MID AF: 0.675

Gnomad NFE AF: 0.597

Gnomad OTH AF: 0.609

GnomAD3 exomes AF: 0.503 AC: 115608 AN: 229936 Hom.: 32150 AF XY: 0.510 AC XY: 63387 AN XY: 124218

Gnomad AFR exome AF: 0.715

Gnomad AMR exome AF: 0.302

Gnomad ASJ exome AF: 0.632

Gnomad EAS exome AF: 0.0931

Gnomad SAS exome AF: 0.460

Gnomad FIN exome AF: 0.488

Gnomad NFE exome AF: 0.600

Gnomad OTH exome AF: 0.552

GnomAD4 exome AF: 0.566 AC: 809978 AN: 1431698 Hom.: 238291 Cov.: 25 AF XY: 0.565 AC XY: 402130 AN XY: 712306

Gnomad4 AFR exome AF: 0.720

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.632

Gnomad4 EAS exome AF: 0.0623

Gnomad4 SAS exome AF: 0.458

Gnomad4 FIN exome AF: 0.488

Gnomad4 NFE exome AF: 0.598

Gnomad4 OTH exome AF: 0.571

GnomAD4 genome AF: 0.582 AC: 88562 AN: 152122 Hom.: 27130 Cov.: 33 AF XY: 0.568 AC XY: 42233 AN XY: 74358

Gnomad4 AFR AF: 0.707

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.0914

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.467

Gnomad4 NFE AF: 0.597

Gnomad4 OTH AF: 0.605

Alfa AF: 0.591 Hom.: 6804

Bravo AF: 0.583

Asia WGS AF: 0.311 AC: 1081 AN: 3478

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 65% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. 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

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	5.2
Dann	Benign	0.72
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs4622692; hg19: chr2-9633137;