2-9490102-C-T

Variant names:

• chr2-9490102-C-T
• rs6705408
• NM_003183.6:c.*75G>A

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.*75G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,353,458 control chromosomes in the GnomAD database, including 228,161 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.58 (27051 hom., cov: 33)
  • Exomes 𝑓: 0.57 (201110 hom.)
• Consequence: ADAM17 NM_003183.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.46
• Publications: 27 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=-0.97).
• BP6: Variant 2-9490102-C-T is Benign according to our data. Variant chr2-9490102-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.699 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.*75G>A		3_prime_UTR	Exon 19 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.*75G>A		3_prime_UTR	Exon 19 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.*75G>A		3_prime_UTR	Exon 19 of 19	NP_001369707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.*75G>A		3_prime_UTR	Exon 19 of 19	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000926352.1		c.*75G>A		3_prime_UTR	Exon 20 of 20	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.*75G>A		3_prime_UTR	Exon 19 of 19	ENSP00000615343.1

Frequencies

GnomAD3 genomes AF: 0.581 AC: 88365 AN: 152016 Hom.: 27020 Cov.: 33

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.729

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.629

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.466

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.608

GnomAD4 exome AF: 0.567 AC: 681305 AN: 1201324 Hom.: 201110 Cov.: 17 AF XY: 0.565 AC XY: 333676 AN XY: 590352

African (AFR) AF: 0.721 AC: 19587 AN: 27182

American (AMR) AF: 0.335 AC: 9229 AN: 27526

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 12182 AN: 19346

East Asian (EAS) AF: 0.0617 AC: 2278 AN: 36894

South Asian (SAS) AF: 0.457 AC: 30053 AN: 65690

European-Finnish (FIN) AF: 0.492 AC: 21972 AN: 44702

Middle Eastern (MID) AF: 0.661 AC: 2328 AN: 3522

European-Non Finnish (NFE) AF: 0.599 AC: 554739 AN: 925854

Other (OTH) AF: 0.572 AC: 28937 AN: 50608

GnomAD4 genome AF: 0.581 AC: 88440 AN: 152134 Hom.: 27051 Cov.: 33 AF XY: 0.567 AC XY: 42163 AN XY: 74376

African (AFR) AF: 0.705 AC: 29268 AN: 41492

American (AMR) AF: 0.445 AC: 6796 AN: 15288

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

East Asian (EAS) AF: 0.0911 AC: 472 AN: 5182

South Asian (SAS) AF: 0.437 AC: 2108 AN: 4828

European-Finnish (FIN) AF: 0.466 AC: 4929 AN: 10570

Middle Eastern (MID) AF: 0.673 AC: 198 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40549 AN: 67990

Other (OTH) AF: 0.604 AC: 1272 AN: 2106

Alfa AF: 0.588 Hom.: 43831

Bravo AF: 0.583

Asia WGS AF: 0.310 AC: 1078 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inflammatory skin and bowel disease, neonatal, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.048
DANN	Benign	0.39
PhyloP100		-1.5
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: rs6705408; hg19: chr2-9630231; COSMIC: COSV60398343; COSMIC: COSV60398343;