rs61754178

chr2-9543235-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003183.6(ADAM17):c.148A>G(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 (★★).

• Frequency:
  • Genomes: 𝑓 0.0042 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0046 (24 hom.)
• Consequence: ADAM17 NM_003183.6 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• 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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 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: 641 AN: 152148 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00595

Gnomad OTH AF: 0.00812

GnomAD3 exomes AF: 0.00376 AC: 932 AN: 248098 Hom.: 5 AF XY: 0.00384 AC XY: 515 AN XY: 134124

Gnomad AFR exome AF: 0.000620

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.000900

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000771

Gnomad FIN exome AF: 0.00372

Gnomad NFE exome AF: 0.00554

Gnomad OTH exome AF: 0.00315

GnomAD4 exome AF: 0.00459 AC: 6687 AN: 1457750 Hom.: 24 Cov.: 30 AF XY: 0.00449 AC XY: 3257 AN XY: 725242

Gnomad4 AFR exome AF: 0.000631

Gnomad4 AMR exome AF: 0.00482

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000947

Gnomad4 FIN exome AF: 0.00389

Gnomad4 NFE exome AF: 0.00533

Gnomad4 OTH exome AF: 0.00355

GnomAD4 genome AF: 0.00420 AC: 639 AN: 152266 Hom.: 1 Cov.: 33 AF XY: 0.00423 AC XY: 315 AN XY: 74460

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00752

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00594

Gnomad4 OTH AF: 0.00803

Alfa AF: 0.00480 Hom.: 6

Bravo AF: 0.00412

TwinsUK AF: 0.00405 AC: 15

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00419 AC: 36

ExAC AF: 0.00368 AC: 447

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	ADAM17: BS2 -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	19
Dann	Uncertain	1.0
DEOGEN2	Benign	0.051	T;T;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.0068	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M;M;.
MutationTaster	Benign	0.77	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.57	N;N;.
REVEL	Benign	0.11
Sift	Benign	0.30	T;T;.
Sift4G	Benign	0.12	T;T;.
Polyphen		0.62	P;P;.
Vest4		0.49
MVP		0.45
MPC		0.59
ClinPred		0.034	T
GERP RS		5.3
Varity_R		0.14
gMVP		0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61754178; hg19: chr2-9683364; COSMIC: COSV99072205;