rs1130094

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr2-9489887-T-A
• chr2-9489887-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003183.6(ADAM17):​c.*290A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ADAM17 NM_003183.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.*290A>T		3_prime_UTR_variant	Exon 19 of 19	ENST00000310823.8	NP_003174.3
IAH1	NM_001039613.3	c.*1558T>A		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>T		3_prime_UTR_variant	Exon 19 of 19	1	NM_003183.6	ENSP00000309968.3
IAH1	ENST00000497473.6	c.*1558T>A		downstream_gene_variant		1	NM_001039613.3	ENSP00000417580.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000618 AC: 1 AN: 161782 Hom.: 0 Cov.: 2 AF XY: 0.00 AC XY: 0 AN XY: 82366

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 6498

American (AMR) AF: 0.00 AC: 0 AN: 7402

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5972

East Asian (EAS) AF: 0.00 AC: 0 AN: 14160

South Asian (SAS) AF: 0.00 AC: 0 AN: 6652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8800

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 101124

Other (OTH) AF: 0.0000958 AC: 1 AN: 10438

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 21440

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.1
DANN	Benign	0.80
PhyloP100		0.30

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;