2-9555777-A-T

Variant names:

• chr2-9555777-A-T
• rs12692386
• ENST00000618923.2:n.-172T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000618923.2(ADAM17):​n.-172T>A 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 0.00000287 in 348,958 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ADAM17 ENST00000618923.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.89
• Publications: 0 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

ENSG00000271855 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.-172T>A		5_prime_UTR_variant	Exon 1 of 19	ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-852T>A		5_prime_UTR_variant	Exon 1 of 19		NP_001369706.1
ADAM17	NM_001382778.1	c.-1094T>A		5_prime_UTR_variant	Exon 1 of 19		NP_001369707.1
ADAM17	XM_047445610.1	c.-330T>A		5_prime_UTR_variant	Exon 1 of 20		XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000618923.2	n.-172T>A		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000480552.1
ADAM17	ENST00000310823.8	c.-172T>A		5_prime_UTR_variant	Exon 1 of 19	1	NM_003183.6	ENSP00000309968.3
ADAM17	ENST00000618923.2	n.-172T>A		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000480552.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000287 AC: 1 AN: 348958 Hom.: 0 Cov.: 5 AF XY: 0.00000555 AC XY: 1 AN XY: 180286

African (AFR) AF: 0.00 AC: 0 AN: 9004

American (AMR) AF: 0.00 AC: 0 AN: 10268

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10412

East Asian (EAS) AF: 0.00 AC: 0 AN: 24240

South Asian (SAS) AF: 0.0000516 AC: 1 AN: 19392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1498

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 228902

Other (OTH) AF: 0.00 AC: 0 AN: 19982

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	20
DANN	Benign	0.90
PhyloP100		1.9
PromoterAI		-0.12	Neutral

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: rs12692386; hg19: chr2-9695906;