chr2-9521321-A-G

Variant names:

• chr2-9521321-A-G
• rs201461814
• NM_003183.6:c.844-5T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_003183.6(ADAM17):​c.844-5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00842 in 1,566,064 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (6 hom., cov: 31)
  • Exomes 𝑓: 0.0087 (68 hom.)
• Consequence: ADAM17 NM_003183.6 splice_region, intron
• Scores: Splicing: ADA: 0.6902
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.24
• Publications: 2 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: Labcorp Genetics (formerly Invitae), G2P, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-9521321-A-G is Benign according to our data. Variant chr2-9521321-A-G is described in ClinVar as Benign. ClinVar VariationId is 539951.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00601 (915/152250) while in subpopulation NFE AF = 0.00973 (662/68022). AF 95% confidence interval is 0.00912. There are 6 homozygotes in GnomAd4. There are 402 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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.844-5T>C		splice_region intron	N/A	NP_003174.3
	ADAM17	NM_001382778.1		c.-59T>C		splice_region	Exon 8 of 19	NP_001369707.1
	ADAM17	NM_001382778.1		c.-59T>C		5_prime_UTR	Exon 8 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.844-5T>C		splice_region intron	N/A	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000926352.1		c.922-5T>C		splice_region intron	N/A	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.844-5T>C		splice_region intron	N/A	ENSP00000615343.1

Frequencies

GnomAD3 genomes AF: 0.00601 AC: 914 AN: 152132 Hom.: 6 Cov.: 31

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00596

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00973

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00661 AC: 1659 AN: 250990 AF XY: 0.00641

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00541

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00835

GnomAD4 exome AF: 0.00868 AC: 12274 AN: 1413814 Hom.: 68 Cov.: 26 AF XY: 0.00848 AC XY: 5988 AN XY: 706054

African (AFR) AF: 0.00161 AC: 52 AN: 32334

American (AMR) AF: 0.00392 AC: 175 AN: 44606

Ashkenazi Jewish (ASJ) AF: 0.00450 AC: 116 AN: 25784

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39428

South Asian (SAS) AF: 0.00255 AC: 217 AN: 85232

European-Finnish (FIN) AF: 0.00569 AC: 303 AN: 53246

Middle Eastern (MID) AF: 0.00212 AC: 12 AN: 5670

European-Non Finnish (NFE) AF: 0.0103 AC: 11001 AN: 1068776

Other (OTH) AF: 0.00676 AC: 397 AN: 58738

GnomAD4 genome AF: 0.00601 AC: 915 AN: 152250 Hom.: 6 Cov.: 31 AF XY: 0.00540 AC XY: 402 AN XY: 74442

African (AFR) AF: 0.00173 AC: 72 AN: 41538

American (AMR) AF: 0.00602 AC: 92 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4828

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00973 AC: 662 AN: 68022

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00817 Hom.: 1

Bravo AF: 0.00568

Asia WGS AF: 0.000577 AC: 2 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.95
PhyloP100		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
SpliceAI score (max)		0.030		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: rs201461814; hg19: chr2-9661450;