2-9555759-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_003183.6(ADAM17):c.-154C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 587,790 control chromosomes in the GnomAD database, including 9,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.16 ( 2069 hom., cov: 32)

Exomes 𝑓: 0.17 ( 7301 hom. )

Consequence

ADAM17
NM_003183.6 5_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0100

Publications

21 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 Gene-Disease associations (from GenCC):

inflammatory skin and bowel disease, neonatal, 1
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
neonatal inflammatory skin and bowel disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ADAM17 links:

ENSG00000271855 (HGNC:):

ENSG00000271855 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP6

Variant 2-9555759-G-T is Benign according to our data. Variant chr2-9555759-G-T is described in ClinVar as Benign. ClinVar VariationId is 1279750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

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.-154C>A	5_prime_UTR	Exon 1 of 19	NP_003174.3
ADAM17	NM_001382777.1		c.-834C>A	5_prime_UTR	Exon 1 of 19	NP_001369706.1
ADAM17	NM_001382778.1		c.-1076C>A	5_prime_UTR	Exon 1 of 19	NP_001369707.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.-154C>A	5_prime_UTR	Exon 1 of 19	ENSP00000309968.3	P78536-1
ADAM17	ENST00000478059.1	TSL:1	n.16C>A	non_coding_transcript_exon	Exon 1 of 5
ADAM17	ENST00000618923.2	TSL:1	n.-154C>A	non_coding_transcript_exon	Exon 1 of 8	ENSP00000480552.1	A6H8L4

Frequencies

GnomAD3 genomes

AF:

0.156

AC:

23676

AN:

152098

Hom.:

2070

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0972

Gnomad AMI

AF:

0.392

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.231

Gnomad EAS

AF:

0.0255

Gnomad SAS

AF:

0.0949

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.277

Gnomad NFE

AF:

0.202

Gnomad OTH

AF:

0.172

GnomAD4 exome

AF:

0.172

AC:

74839

AN:

435574

Hom.:

7301

Cov.:

AF XY:

0.170

AC XY:

37847

AN XY:

222672

show subpopulations

African (AFR)

AF:

0.0927

AC:

986

AN:

10642

American (AMR)

AF:

0.126

AC:

1390

AN:

11016

Ashkenazi Jewish (ASJ)

AF:

0.230

AC:

2556

AN:

11118

East Asian (EAS)

AF:

0.0195

AC:

487

AN:

24926

South Asian (SAS)

AF:

0.0953

AC:

2243

AN:

23524

European-Finnish (FIN)

AF:

0.159

AC:

4522

AN:

28364

Middle Eastern (MID)

AF:

0.245

AC:

418

AN:

1708

European-Non Finnish (NFE)

AF:

0.193

AC:

58172

AN:

301216

Other (OTH)

AF:

0.176

AC:

4065

AN:

23060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

3163

6326

9490

12653

15816

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1094

2188

3282

4376

5470

<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:

0.156

AC:

23670

AN:

152216

Hom.:

2069

Cov.:

AF XY:

0.152

AC XY:

11292

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.0970

AC:

4030

AN:

41544

American (AMR)

AF:

0.141

AC:

2150

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.231

AC:

801

AN:

3470

East Asian (EAS)

AF:

0.0253

AC:

131

AN:

5174

South Asian (SAS)

AF:

0.0948

AC:

457

AN:

4820

European-Finnish (FIN)

AF:

0.150

AC:

1590

AN:

10606

Middle Eastern (MID)

AF:

0.281

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.202

AC:

13713

AN:

67992

Other (OTH)

AF:

0.170

AC:

359

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

1042

2084

3126

4168

5210

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

246

492

738

984

1230

<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:

0.167

Hom.:

350

Bravo

AF:

0.156

Asia WGS

AF:

0.0810

AC:

285

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Mycobacterium tuberculosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.57

PhyloP100

0.010

PromoterAI

-0.037

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=299/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.23

Position offset: -1

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