chr2-9502349-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003183.6(ADAM17):c.1545-73G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,310,460 control chromosomes in the GnomAD database, including 151,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14253 hom., cov: 31)

Exomes 𝑓: 0.47 ( 136771 hom. )

Consequence

ADAM17
NM_003183.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -3.44

Publications

12 publications found

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:

ENSG00000239300 (HGNC:):

ENSG00000239300 links:

IAH1 (HGNC:27696): (isoamyl acetate hydrolyzing esterase 1 (putative)) Enables identical protein binding activity. Predicted to be involved in lipid catabolic process. [provided by Alliance of Genome Resources, Apr 2022]

IAH1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 2-9502349-C-T is Benign according to our data. Variant chr2-9502349-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6 link	c.1545-73G>A		intron_variant	Intron 12 of 18	ENST00000310823.8	NP_003174.3	P78536-1B2RNB2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8 link	c.1545-73G>A		intron_variant	Intron 12 of 18	1	NM_003183.6	ENSP00000309968.3		P78536-1

Frequencies

GnomAD3 genomes

AF:

0.416

AC:

63080

AN:

151742

Hom.:

14257

Cov.:

show subpopulations

Gnomad AFR

AF:

0.306

Gnomad AMI

AF:

0.684

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.549

Gnomad EAS

AF:

0.0303

Gnomad SAS

AF:

0.343

Gnomad FIN

AF:

0.439

Gnomad MID

AF:

0.614

Gnomad NFE

AF:

0.514

Gnomad OTH

AF:

0.468

GnomAD4 exome

AF:

0.473

AC:

547772

AN:

1158600

Hom.:

136771

AF XY:

0.472

AC XY:

277357

AN XY:

587216

show subpopulations

African (AFR)

AF:

0.311

AC:

8509

AN:

27342

American (AMR)

AF:

0.257

AC:

10797

AN:

41944

Ashkenazi Jewish (ASJ)

AF:

0.551

AC:

12714

AN:

23092

East Asian (EAS)

AF:

0.0232

AC:

884

AN:

38078

South Asian (SAS)

AF:

0.366

AC:

28425

AN:

77564

European-Finnish (FIN)

AF:

0.456

AC:

18866

AN:

41382

Middle Eastern (MID)

AF:

0.600

AC:

2724

AN:

4540

European-Non Finnish (NFE)

AF:

0.516

AC:

441095

AN:

854150

Other (OTH)

AF:

0.470

AC:

23758

AN:

50508

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

13344

26687

40031

53374

66718

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11114

22228

33342

44456

55570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.416

AC:

63106

AN:

151860

Hom.:

14253

Cov.:

AF XY:

0.407

AC XY:

30232

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.307

AC:

12688

AN:

41394

American (AMR)

AF:

0.352

AC:

5369

AN:

15242

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

1904

AN:

3470

East Asian (EAS)

AF:

0.0302

AC:

156

AN:

5166

South Asian (SAS)

AF:

0.342

AC:

1650

AN:

4818

European-Finnish (FIN)

AF:

0.439

AC:

4616

AN:

10526

Middle Eastern (MID)

AF:

0.616

AC:

181

AN:

294

European-Non Finnish (NFE)

AF:

0.514

AC:

34935

AN:

67926

Other (OTH)

AF:

0.465

AC:

983

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1768

3536

5304

7072

8840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

574

1148

1722

2296

2870

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.447

Hom.:

2840

Bravo

AF:

0.403

Asia WGS

AF:

0.204

AC:

708

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Nov 10, 2018

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

- -

not specified

Benign:1

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 49% of patients studied by a panel of primary immunodeficiencies. Number of patients: 47. Only high quality variants are reported. -

Inflammatory skin and bowel disease, neonatal, 1

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.0090

(source)

DANN

Benign

0.85

PhyloP100

-3.4

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over