2-9489887-T-C

Variant names:

• chr2-9489887-T-C
• rs1130094
• NM_003183.6:c.*290A>G

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.*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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.303
• Publications: 15 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: 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 VariationId is 1278966.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 rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.*290A>G		3_prime_UTR_variant	Exon 19 of 19	ENST00000310823.8	NP_003174.3
IAH1	NM_001039613.3	c.*1558T>C		downstream_gene_variant		ENST00000497473.6	NP_001034702.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.*290A>G		3_prime_UTR_variant	Exon 19 of 19	1	NM_003183.6	ENSP00000309968.3
IAH1	ENST00000497473.6	c.*1558T>C		downstream_gene_variant		1	NM_001039613.3	ENSP00000417580.1

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

African (AFR) AF: 0.309 AC: 2009 AN: 6492

American (AMR) AF: 0.311 AC: 2297 AN: 7378

Ashkenazi Jewish (ASJ) AF: 0.546 AC: 3247 AN: 5948

East Asian (EAS) AF: 0.0220 AC: 312 AN: 14156

South Asian (SAS) AF: 0.363 AC: 2411 AN: 6634

European-Finnish (FIN) AF: 0.455 AC: 3983 AN: 8756

Middle Eastern (MID) AF: 0.584 AC: 426 AN: 730

European-Non Finnish (NFE) AF: 0.517 AC: 52100 AN: 100788

Other (OTH) AF: 0.474 AC: 4936 AN: 10406

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

African (AFR) AF: 0.310 AC: 12842 AN: 41444

American (AMR) AF: 0.352 AC: 5379 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1890 AN: 3470

East Asian (EAS) AF: 0.0297 AC: 154 AN: 5188

South Asian (SAS) AF: 0.344 AC: 1659 AN: 4828

European-Finnish (FIN) AF: 0.438 AC: 4607 AN: 10510

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34949 AN: 67970

Other (OTH) AF: 0.468 AC: 984 AN: 2104

Alfa AF: 0.498 Hom.: 21440

Bravo AF: 0.404

Asia WGS AF: 0.206 AC: 715 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	8.0
DANN	Benign	0.81
PhyloP100		0.30
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1130094; hg19: chr2-9630016;