2-9527801-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.064 ( 1104 hom., cov: 33)

Exomes 𝑓: 0.0065 ( 929 hom. )

Consequence

ADAM17
NM_003183.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.230

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=0.0019344985).

BP6

Variant 2-9527801-T-C is Benign according to our data. Variant chr2-9527801-T-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6 link	c.604A>G	p.Arg202Gly	missense_variant	Exon 5 of 19	ENST00000310823.8	NP_003174.3	P78536-1B2RNB2
ADAM17	XM_047445610.1 link	c.511A>G	p.Arg171Gly	missense_variant	Exon 6 of 20		XP_047301566.1
ADAM17	NM_001382777.1 link	c.-77A>G		5_prime_UTR_variant	Exon 5 of 19		NP_001369706.1
ADAM17	NM_001382778.1 link	c.-319A>G		5_prime_UTR_variant	Exon 5 of 19		NP_001369707.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8 link	c.604A>G	p.Arg202Gly	missense_variant	Exon 5 of 19	1	NM_003183.6	ENSP00000309968.3		P78536-1
ADAM17	ENST00000618923.2 link	n.604A>G		non_coding_transcript_exon_variant	Exon 5 of 8	1		ENSP00000480552.1		A6H8L4

Frequencies

GnomAD3 genomes

AF:

0.0641

AC:

9747

AN:

152170

Hom.:

1099

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0165

AC:

3740

AN:

226884

Hom.:

380

AF XY:

0.0119

AC XY:

1463

AN XY:

123364

show subpopulations

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 SAS exome

AF:

0.000988

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.:

AF XY:

0.00561

AC XY:

3986

AN XY:

709980

show subpopulations

Gnomad4 AFR exome

AF:

0.229

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.0000395

Gnomad4 EAS exome

AF:

0.0000522

Gnomad4 SAS exome

AF:

0.000994

Gnomad4 FIN exome

AF:

0.0000379

Gnomad4 NFE exome

AF:

0.000417

Gnomad4 OTH exome

AF:

0.0153

GnomAD4 genome

AF:

0.0641

AC:

9766

AN:

152288

Hom.:

1104

Cov.:

AF XY:

0.0617

AC XY:

4598

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.221

Gnomad4 AMR

AF:

0.0272

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00103

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00103

Gnomad4 OTH

AF:

0.0454

Alfa

AF:

0.0199

Hom.:

248

Bravo

AF:

0.0732

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.223

AC:

982

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.0201

AC:

2439

Asia WGS

AF:

0.0160

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Inflammatory skin and bowel disease, neonatal, 1

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.64

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.62

.;T

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.2

N;N

REVEL

Benign

0.032

Sift

Benign

0.27

T;T

Sift4G

Benign

0.25

T;T

Polyphen

0.0

B;B

Vest4

0.050

MPC

0.49

ClinPred

0.0014

GERP RS

2.8

Varity_R

0.16

gMVP

0.80

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

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