rs61754178

Positions:

chr2-9543235-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 5.44

Variant links:

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 links:

Genome browser will be placed here

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	Protein
ADAM17	NM_003183.6 linkuse as main transcript	c.148A>G	p.Ile50Val	missense_variant	2/19	ENST00000310823.8	NP_003174.3
ADAM17	XM_047445610.1 linkuse as main transcript	c.55A>G	p.Ile19Val	missense_variant	3/20		XP_047301566.1
ADAM17	NM_001382777.1 linkuse as main transcript	c.-533A>G		5_prime_UTR_variant	2/19		NP_001369706.1
ADAM17	NM_001382778.1 linkuse as main transcript	c.-775A>G		5_prime_UTR_variant	2/19		NP_001369707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8 linkuse as main transcript	c.148A>G	p.Ile50Val	missense_variant	2/19	1	NM_003183.6	ENSP00000309968	P1	P78536-1

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

641

AN:

152148

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00384

AC XY:

515

AN XY:

134124

show subpopulations

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.:

Cov.:

AF XY:

0.00449

AC XY:

3257

AN XY:

725242

show subpopulations

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.:

Cov.:

AF XY:

0.00423

AC XY:

315

AN XY:

74460

show subpopulations

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.:

Bravo

AF:

0.00412

TwinsUK

AF:

0.00405

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00419

AC:

ExAC

AF:

0.00368

AC:

447

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

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	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ADAM17-related disorder

Benign:1

Likely benign, no assertion criteria provided

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.094

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.051

T;T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Benign

0.0042

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

0.77

D;D

PrimateAI

Uncertain

0.58

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over