2-9527801-T-C

Variant names:

• chr2-9527801-T-C
• rs2230818
• NM_003183.6:c.604A>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.604A>G​(p.Arg202Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0121 in 1,581,208 control chromosomes in the GnomAD database, including 2,033 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R202K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.064 (1104 hom., cov: 33)
  • Exomes 𝑓: 0.0065 (929 hom.)
• Consequence: ADAM17 NM_003183.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.230
• Publications: 10 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 (MetaRNN=0.0019344985).
• BP6: Variant 2-9527801-T-C is Benign according to our data. Variant chr2-9527801-T-C is described in ClinVar as Benign. ClinVar VariationId is 472727.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.604A>G	p.Arg202Gly	missense	Exon 5 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.-77A>G		5_prime_UTR	Exon 5 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.-319A>G		5_prime_UTR	Exon 5 of 19	NP_001369707.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.604A>G	p.Arg202Gly	missense	Exon 5 of 19	ENSP00000309968.3
	ADAM17	ENST00000478059.1	TSL:1	n.773A>G		non_coding_transcript_exon	Exon 5 of 5
	ADAM17	ENST00000618923.2	TSL:1	n.604A>G		non_coding_transcript_exon	Exon 5 of 8	ENSP00000480552.1

Frequencies

GnomAD3 genomes AF: 0.0641 AC: 9747 AN: 152170 Hom.: 1099 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00103

Gnomad OTH AF: 0.0458

GnomAD2 exomes AF: 0.0165 AC: 3740 AN: 226884 AF XY: 0.0119

Gnomad AFR exome AF: 0.221

Gnomad AMR exome AF: 0.0109

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000120

Gnomad FIN exome AF: 0.0000945

Gnomad NFE exome AF: 0.000550

Gnomad OTH exome AF: 0.00805

GnomAD4 exome AF: 0.00651 AC: 9299 AN: 1428920 Hom.: 929 Cov.: 30 AF XY: 0.00561 AC XY: 3986 AN XY: 709980

African (AFR) AF: 0.229 AC: 7290 AN: 31800

American (AMR) AF: 0.0131 AC: 496 AN: 37942

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25320

East Asian (EAS) AF: 0.0000522 AC: 2 AN: 38310

South Asian (SAS) AF: 0.000994 AC: 78 AN: 78442

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52776

Middle Eastern (MID) AF: 0.0125 AC: 71 AN: 5678

European-Non Finnish (NFE) AF: 0.000417 AC: 458 AN: 1099630

Other (OTH) AF: 0.0153 AC: 901 AN: 59022

GnomAD4 genome AF: 0.0641 AC: 9766 AN: 152288 Hom.: 1104 Cov.: 33 AF XY: 0.0617 AC XY: 4598 AN XY: 74484

African (AFR) AF: 0.221 AC: 9176 AN: 41530

American (AMR) AF: 0.0272 AC: 416 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00103 AC: 5 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00103 AC: 70 AN: 68022

Other (OTH) AF: 0.0454 AC: 96 AN: 2116

Alfa AF: 0.0358 Hom.: 725

Bravo AF: 0.0732

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.223 AC: 982

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.0201 AC: 2439

Asia WGS AF: 0.0160 AC: 57 AN: 3476

ClinVar

ClinVar submissions as Germline

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
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Benign	0.95
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.23
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.032
Sift	Benign	0.27	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.050
MPC		0.49
ClinPred		0.0014	T
GERP RS		2.8
Varity_R		0.16
gMVP		0.80
Mutation Taster		=94/6	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: rs2230818; hg19: chr2-9667930; COSMIC: COSV107397536;