dbSNP rs55794209: ADAM17:c.1345-138G>T (chr2-9505503-C-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_003183.6(ADAM17):c.1345-138G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 812,398 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.032 ( 111 hom., cov: 32)

Exomes 𝑓: 0.038 ( 632 hom. )

Consequence

ADAM17
NM_003183.6 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.488

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 2-9505503-C-A is Benign according to our data. Variant chr2-9505503-C-A is described in ClinVar as Benign. ClinVar VariationId is 1183199.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0319 (4852/152154) while in subpopulation NFE AF = 0.0466 (3167/67982). AF 95% confidence interval is 0.0452. There are 111 homozygotes in GnomAd4. There are 2388 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 111 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
ADAM17	NM_003183.6	MANE Select	c.1345-138G>T	intron	N/A	NP_003174.3
ADAM17	NM_001382777.1		c.685-138G>T	intron	N/A	NP_001369706.1
ADAM17	NM_001382778.1		c.448-138G>T	intron	N/A	NP_001369707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.1345-138G>T	intron	N/A	ENSP00000309968.3	P78536-1
ADAM17	ENST00000926352.1		c.1423-138G>T	intron	N/A	ENSP00000596411.1
ADAM17	ENST00000945284.1		c.1375-138G>T	intron	N/A	ENSP00000615343.1

Frequencies

GnomAD3 genomes

AF:

0.0319

AC:

4851

AN:

152036

Hom.:

111

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00739

Gnomad AMI

AF:

0.0615

Gnomad AMR

AF:

0.0187

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.0822

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0466

Gnomad OTH

AF:

0.0282

GnomAD4 exome

AF:

0.0384

AC:

25384

AN:

660244

Hom.:

632

Cov.:

AF XY:

0.0377

AC XY:

12921

AN XY:

342818

show subpopulations

African (AFR)

AF:

0.00714

AC:

121

AN:

16940

American (AMR)

AF:

0.0132

AC:

367

AN:

27838

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

398

AN:

16988

East Asian (EAS)

AF:

0.0000310

AC:

AN:

32296

South Asian (SAS)

AF:

0.00699

AC:

382

AN:

54626

European-Finnish (FIN)

AF:

0.0804

AC:

2614

AN:

32526

Middle Eastern (MID)

AF:

0.00395

AC:

AN:

2530

European-Non Finnish (NFE)

AF:

0.0458

AC:

20289

AN:

443266

Other (OTH)

AF:

0.0362

AC:

1202

AN:

33234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

1277

2554

3831

5108

6385

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

386

772

1158

1544

1930

<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:

0.0319

AC:

4852

AN:

152154

Hom.:

111

Cov.:

AF XY:

0.0321

AC XY:

2388

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00737

AC:

306

AN:

41534

American (AMR)

AF:

0.0186

AC:

285

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5184

South Asian (SAS)

AF:

0.00477

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0822

AC:

869

AN:

10566

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0466

AC:

3167

AN:

67982

Other (OTH)

AF:

0.0279

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

241

482

723

964

1205

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0426

Hom.:

Bravo

AF:

0.0250

Asia WGS

AF:

0.00318

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.67

(source)

DANN

Benign

0.72

PhyloP100

-0.49

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over