chr2-9489887-T-C

Position:

• chr2-9489887-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003183.6(ADAM17):​c.*290A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.431 in 313,280 control chromosomes in the GnomAD database, including 32,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.42 (14306 hom., cov: 32)
  • Exomes 𝑓: 0.44 (18022 hom.)
• Consequence: ADAM17 NM_003183.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.303

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-9489887-T-C is Benign according to our data. Variant chr2-9489887-T-C is described in ClinVar as [Benign]. Clinvar id is 1278966.Status of the report is criteria_provided_single_submitter, 1 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	UniProt
ADAM17	NM_003183.6	c.*290A>G		3_prime_UTR_variant	19/19	ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8	c.*290A>G		3_prime_UTR_variant	19/19	1	NM_003183.6	P1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63234 AN: 151874 Hom.: 14302 Cov.: 32

Gnomad AFR AF: 0.309

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.0298

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.438

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.471

GnomAD4 exome AF: 0.445 AC: 71721 AN: 161288 Hom.: 18022 Cov.: 2 AF XY: 0.448 AC XY: 36798 AN XY: 82116

Gnomad4 AFR exome AF: 0.309

Gnomad4 AMR exome AF: 0.311

Gnomad4 ASJ exome AF: 0.546

Gnomad4 EAS exome AF: 0.0220

Gnomad4 SAS exome AF: 0.363

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.517

Gnomad4 OTH exome AF: 0.474

GnomAD4 genome AF: 0.416 AC: 63269 AN: 151992 Hom.: 14306 Cov.: 32 AF XY: 0.408 AC XY: 30307 AN XY: 74282

Gnomad4 AFR AF: 0.310

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.545

Gnomad4 EAS AF: 0.0297

Gnomad4 SAS AF: 0.344

Gnomad4 FIN AF: 0.438

Gnomad4 NFE AF: 0.514

Gnomad4 OTH AF: 0.468

Alfa AF: 0.503 Hom.: 17936

Bravo AF: 0.404

Asia WGS AF: 0.206 AC: 715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 10, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.0
DANN	Benign	0.81

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: rs1130094; hg19: chr2-9630016;