rs4328603

Variant names:

• chr2-9521055-T-C
• rs4328603
• NM_003183.6:c.957+148A>G

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.957+148A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.587 in 463,832 control chromosomes in the GnomAD database, including 87,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (31406 hom., cov: 26)
  • Exomes 𝑓: 0.57 (55994 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.670
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 2-9521055-T-C is Benign according to our data. Variant chr2-9521055-T-C is described in ClinVar as Benign. ClinVar VariationId is 1263774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.957+148A>G		intron_variant	Intron 8 of 18	ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.957+148A>G		intron_variant	Intron 8 of 18	1	NM_003183.6	ENSP00000309968.3

Frequencies

GnomAD3 genomes AF: 0.632 AC: 94546 AN: 149540 Hom.: 31375 Cov.: 26

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.850

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.690

Gnomad EAS AF: 0.0905

Gnomad SAS AF: 0.444

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.752

Gnomad NFE AF: 0.677

Gnomad OTH AF: 0.657

GnomAD4 exome AF: 0.565 AC: 177634 AN: 314174 Hom.: 55994 AF XY: 0.564 AC XY: 95142 AN XY: 168636

African (AFR) AF: 0.717 AC: 5999 AN: 8364

American (AMR) AF: 0.379 AC: 4585 AN: 12086

Ashkenazi Jewish (ASJ) AF: 0.668 AC: 5852 AN: 8754

East Asian (EAS) AF: 0.0484 AC: 1201 AN: 24796

South Asian (SAS) AF: 0.434 AC: 11665 AN: 26880

European-Finnish (FIN) AF: 0.531 AC: 16662 AN: 31350

Middle Eastern (MID) AF: 0.736 AC: 2064 AN: 2806

European-Non Finnish (NFE) AF: 0.656 AC: 119279 AN: 181854

Other (OTH) AF: 0.597 AC: 10327 AN: 17284

GnomAD4 genome AF: 0.632 AC: 94621 AN: 149658 Hom.: 31406 Cov.: 26 AF XY: 0.616 AC XY: 44899 AN XY: 72908

African (AFR) AF: 0.718 AC: 29192 AN: 40660

American (AMR) AF: 0.487 AC: 7254 AN: 14904

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 2380 AN: 3448

East Asian (EAS) AF: 0.0901 AC: 466 AN: 5172

South Asian (SAS) AF: 0.443 AC: 2093 AN: 4722

European-Finnish (FIN) AF: 0.520 AC: 5268 AN: 10132

Middle Eastern (MID) AF: 0.755 AC: 222 AN: 294

European-Non Finnish (NFE) AF: 0.677 AC: 45641 AN: 67372

Other (OTH) AF: 0.653 AC: 1343 AN: 2058

Alfa AF: 0.673 Hom.: 4503

Bravo AF: 0.634

Asia WGS AF: 0.316 AC: 1102 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.45
DANN	Benign	0.31
PhyloP100		-0.67
Mutation Taster		=99/1	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: rs4328603; hg19: chr2-9661184; COSMIC: COSV60401800; COSMIC: COSV60401800;