2-9493008-T-G

Variant names:

• chr2-9493008-T-G
• rs4622692
• NM_003183.6:c.1994-22A>C

Variant summary

Our verdict is Benign. The variant received -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 (★★). There are indicators that this mutation may affect the branch point..

• 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:4
• Conservation: PhyloP100: -2.39
• Publications: 18 publications found

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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 3 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. 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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.1994-22A>C		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.1334-22A>C		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.1097-22A>C		intron	N/A	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.1994-22A>C		intron	N/A	ENSP00000309968.3
	ADAM17	ENST00000649798.1		n.146A>C		non_coding_transcript_exon	Exon 1 of 3
	ADAM17	ENST00000699318.1		c.1904-22A>C		intron	N/A	ENSP00000514297.1

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

GnomAD2 exomes AF: 0.503 AC: 115608 AN: 229936 AF XY: 0.510

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 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

African (AFR) AF: 0.720 AC: 23194 AN: 32212

American (AMR) AF: 0.317 AC: 13483 AN: 42484

Ashkenazi Jewish (ASJ) AF: 0.632 AC: 16283 AN: 25744

East Asian (EAS) AF: 0.0623 AC: 2413 AN: 38712

South Asian (SAS) AF: 0.458 AC: 37940 AN: 82778

European-Finnish (FIN) AF: 0.488 AC: 25825 AN: 52888

Middle Eastern (MID) AF: 0.670 AC: 3828 AN: 5716

European-Non Finnish (NFE) AF: 0.598 AC: 653145 AN: 1091858

Other (OTH) AF: 0.571 AC: 33867 AN: 59306

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

African (AFR) AF: 0.707 AC: 29367 AN: 41522

American (AMR) AF: 0.445 AC: 6808 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.629 AC: 2183 AN: 3472

East Asian (EAS) AF: 0.0914 AC: 474 AN: 5184

South Asian (SAS) AF: 0.436 AC: 2100 AN: 4814

European-Finnish (FIN) AF: 0.467 AC: 4932 AN: 10566

Middle Eastern (MID) AF: 0.678 AC: 198 AN: 292

European-Non Finnish (NFE) AF: 0.597 AC: 40559 AN: 67964

Other (OTH) AF: 0.605 AC: 1279 AN: 2114

Alfa AF: 0.593 Hom.: 6990

Bravo AF: 0.583

Asia WGS AF: 0.311 AC: 1081 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.72
PhyloP100		-2.4
BranchPoint Hunter		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4622692; hg19: chr2-9633137;