ENST00000618923.2:n.*434C>T

Variant names:

• chr2-9522081-G-A
• rs10495563
• ENST00000618923.2:n.*434C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000618923.2(ADAM17):​n.*434C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 225,584 control chromosomes in the GnomAD database, including 47,211 homozygotes. 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: 𝑓 0.63 (31965 hom., cov: 33)
  • Exomes 𝑓: 0.62 (15246 hom.)
• Consequence: ADAM17 ENST00000618923.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728
• Publications: 20 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]

ADAM17 Gene-Disease associations (from GenCC):

• inflammatory skin and bowel disease, neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000618923.2. 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.844-765C>T		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.184-765C>T		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.-59-760C>T		intron	N/A	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000618923.2	TSL:1	n.*434C>T		non_coding_transcript_exon	Exon 8 of 8	ENSP00000480552.1
	ADAM17	ENST00000618923.2	TSL:1	n.*434C>T		3_prime_UTR	Exon 8 of 8	ENSP00000480552.1
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.844-765C>T		intron	N/A	ENSP00000309968.3

Frequencies

GnomAD3 genomes AF: 0.634 AC: 96272 AN: 151956 Hom.: 31935 Cov.: 33

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.0915

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.532

Gnomad MID AF: 0.747

Gnomad NFE AF: 0.678

Gnomad OTH AF: 0.658

GnomAD4 exome AF: 0.618 AC: 45406 AN: 73512 Hom.: 15246 Cov.: 0 AF XY: 0.622 AC XY: 22748 AN XY: 36568

African (AFR) AF: 0.740 AC: 2238 AN: 3026

American (AMR) AF: 0.430 AC: 952 AN: 2214

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 2324 AN: 3348

East Asian (EAS) AF: 0.0480 AC: 296 AN: 6168

South Asian (SAS) AF: 0.442 AC: 314 AN: 710

European-Finnish (FIN) AF: 0.576 AC: 1741 AN: 3022

Middle Eastern (MID) AF: 0.693 AC: 280 AN: 404

European-Non Finnish (NFE) AF: 0.688 AC: 33833 AN: 49172

Other (OTH) AF: 0.629 AC: 3428 AN: 5448

GnomAD4 genome AF: 0.634 AC: 96345 AN: 152072 Hom.: 31965 Cov.: 33 AF XY: 0.618 AC XY: 45958 AN XY: 74334

African (AFR) AF: 0.717 AC: 29767 AN: 41496

American (AMR) AF: 0.490 AC: 7482 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2396 AN: 3470

East Asian (EAS) AF: 0.0912 AC: 472 AN: 5178

South Asian (SAS) AF: 0.448 AC: 2161 AN: 4820

European-Finnish (FIN) AF: 0.532 AC: 5612 AN: 10542

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.678 AC: 46081 AN: 67976

Other (OTH) AF: 0.653 AC: 1378 AN: 2110

Alfa AF: 0.649 Hom.: 141555

Bravo AF: 0.631

Asia WGS AF: 0.313 AC: 1091 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.5
DANN	Benign	0.45
PhyloP100		0.73
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: rs10495563; hg19: chr2-9662210;