2-9490102-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.*75G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,353,458 control chromosomes in the GnomAD database, including 228,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27051 hom., cov: 33)
  • Exomes 𝑓: 0.57 (201110 hom.)
• Consequence: ADAM17 NM_003183.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.46

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=-0.97).
• BP6: Variant 2-9490102-C-T is Benign according to our data. Variant chr2-9490102-C-T is described in ClinVar as [Benign]. Clinvar id is 1188895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM17	NM_003183.6	c.*75G>A		3_prime_UTR_variant	19/19	ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.*75G>A		3_prime_UTR_variant	19/19	1	NM_003183.6	P1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88365 AN: 152016 Hom.: 27020 Cov.: 33

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.608

GnomAD4 exome AF: 0.567 AC: 681305 AN: 1201324 Hom.: 201110 Cov.: 17 AF XY: 0.565 AC XY: 333676 AN XY: 590352

Gnomad4 AFR exome AF: 0.721

Gnomad4 AMR exome AF: 0.335

Gnomad4 ASJ exome AF: 0.630

Gnomad4 EAS exome AF: 0.0617

Gnomad4 SAS exome AF: 0.457

Gnomad4 FIN exome AF: 0.492

Gnomad4 NFE exome AF: 0.599

Gnomad4 OTH exome AF: 0.572

GnomAD4 genome AF: 0.581 AC: 88440 AN: 152134 Hom.: 27051 Cov.: 33 AF XY: 0.567 AC XY: 42163 AN XY: 74376

Gnomad4 AFR AF: 0.705

Gnomad4 AMR AF: 0.445

Gnomad4 ASJ AF: 0.629

Gnomad4 EAS AF: 0.0911

Gnomad4 SAS AF: 0.437

Gnomad4 FIN AF: 0.466

Gnomad4 NFE AF: 0.596

Gnomad4 OTH AF: 0.604

Alfa AF: 0.586 Hom.: 34133

Bravo AF: 0.583

Asia WGS AF: 0.310 AC: 1078 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 57% of patients studied by a panel of primary immunodeficiencies. Number of patients: 55. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

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	-0.97
Cadd	Benign	0.048
Dann	Benign	0.39

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: rs6705408; hg19: chr2-9630231; COSMIC: COSV60398343; COSMIC: COSV60398343;