rs61754178
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_003183.6(ADAM17):āc.148A>Gā(p.Ile50Val) variant causes a missense change. The variant allele was found at a frequency of 0.00455 in 1,610,016 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0042 ( 1 hom., cov: 33)
Exomes š: 0.0046 ( 24 hom. )
Consequence
ADAM17
NM_003183.6 missense
NM_003183.6 missense
Scores
6
12
Clinical Significance
Conservation
PhyloP100: 5.44
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0067513883).
BP6
?
Variant 2-9543235-T-C is Benign according to our data. Variant chr2-9543235-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 472722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9543235-T-C is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0042 (639/152266) while in subpopulation AMR AF= 0.00752 (115/15284). AF 95% confidence interval is 0.00641. There are 1 homozygotes in gnomad4. There are 315 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAdExome4 at 24 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ADAM17 | NM_003183.6 | c.148A>G | p.Ile50Val | missense_variant | 2/19 | ENST00000310823.8 | |
ADAM17 | XM_047445610.1 | c.55A>G | p.Ile19Val | missense_variant | 3/20 | ||
ADAM17 | NM_001382777.1 | c.-533A>G | 5_prime_UTR_variant | 2/19 | |||
ADAM17 | NM_001382778.1 | c.-775A>G | 5_prime_UTR_variant | 2/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ADAM17 | ENST00000310823.8 | c.148A>G | p.Ile50Val | missense_variant | 2/19 | 1 | NM_003183.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00421 AC: 641AN: 152148Hom.: 1 Cov.: 33
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00376 AC: 932AN: 248098Hom.: 5 AF XY: 0.00384 AC XY: 515AN XY: 134124
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GnomAD4 exome AF: 0.00459 AC: 6687AN: 1457750Hom.: 24 Cov.: 30 AF XY: 0.00449 AC XY: 3257AN XY: 725242
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GnomAD4 genome ? AF: 0.00420 AC: 639AN: 152266Hom.: 1 Cov.: 33 AF XY: 0.00423 AC XY: 315AN XY: 74460
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20
ESP6500AA
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ESP6500EA
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ClinVar
Significance: Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | ADAM17: BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
ADAM17-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 14, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Inflammatory skin and bowel disease, neonatal, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;.
REVEL
Benign
Sift
Benign
T;T;.
Sift4G
Benign
T;T;.
Polyphen
P;P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at