chr2-9491211-T-C

Position:

• chr2-9491211-T-C

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.2083-60A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.468 in 1,479,208 control chromosomes in the GnomAD database, including 171,241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14292 hom., cov: 32)
  • Exomes 𝑓: 0.47 (156949 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.98

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=-0.91).
• BP6: Variant 2-9491211-T-C is Benign according to our data. Variant chr2-9491211-T-C is described in ClinVar as [Benign]. Clinvar id is 1188897.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.2083-60A>G		intron_variant		ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.2083-60A>G		intron_variant		1	NM_003183.6	ENSP00000309968	P1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63196 AN: 151956 Hom.: 14291 Cov.: 32

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.685

Gnomad AMR AF: 0.355

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.0302

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.474 AC: 629083 AN: 1327134 Hom.: 156949 AF XY: 0.474 AC XY: 315846 AN XY: 666262

Gnomad4 AFR exome AF: 0.311

Gnomad4 AMR exome AF: 0.259

Gnomad4 ASJ exome AF: 0.546

Gnomad4 EAS exome AF: 0.0231

Gnomad4 SAS exome AF: 0.366

Gnomad4 FIN exome AF: 0.456

Gnomad4 NFE exome AF: 0.514

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.416 AC: 63225 AN: 152074 Hom.: 14292 Cov.: 32 AF XY: 0.408 AC XY: 30296 AN XY: 74334

Gnomad4 AFR AF: 0.307

Gnomad4 AMR AF: 0.354

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.0301

Gnomad4 SAS AF: 0.343

Gnomad4 FIN AF: 0.439

Gnomad4 NFE AF: 0.514

Gnomad4 OTH AF: 0.467

Alfa AF: 0.495 Hom.: 38025

Bravo AF: 0.403

Asia WGS AF: 0.206 AC: 717 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 54% of patients studied by a panel of primary immunodeficiencies. Number of patients: 52. 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	-0.91
CADD	Benign	0.17
DANN	Benign	0.70

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: rs10495562; hg19: chr2-9631340;