chr2-9494727-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003183.6(ADAM17):c.1824T>C(p.Ser608Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,613,660 control chromosomes in the GnomAD database, including 270,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.58 ( 27271 hom., cov: 31)

Exomes 𝑓: 0.57 ( 243008 hom. )

Consequence

ADAM17
NM_003183.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.513

Publications

36 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:

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-9494727-A-G is Benign according to our data. Variant chr2-9494727-A-G is described in ClinVar as Benign. ClinVar VariationId is 1169868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.513 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6 link	c.1824T>C	p.Ser608Ser	synonymous_variant	Exon 15 of 19	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.1824T>C	p.Ser608Ser	synonymous_variant	Exon 15 of 19	1	NM_003183.6	ENSP00000309968.3		P78536-1

Frequencies

GnomAD3 genomes

AF:

0.584

AC:

88640

AN:

151888

Hom.:

27239

Cov.:

show subpopulations

Gnomad AFR

AF:

0.712

Gnomad AMI

AF:

0.729

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.629

Gnomad EAS

AF:

0.0926

Gnomad SAS

AF:

0.440

Gnomad FIN

AF:

0.466

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.597

Gnomad OTH

AF:

0.611

GnomAD2 exomes

AF:

0.500

AC:

125705

AN:

251400

AF XY:

0.508

show subpopulations

Gnomad AFR exome

AF:

0.717

Gnomad AMR exome

AF:

0.299

Gnomad ASJ exome

AF:

0.628

Gnomad EAS exome

AF:

0.0920

Gnomad FIN exome

AF:

0.485

Gnomad NFE exome

AF:

0.596

Gnomad OTH exome

AF:

0.555

GnomAD4 exome

AF:

0.565

AC:

826280

AN:

1461654

Hom.:

243008

Cov.:

AF XY:

0.564

AC XY:

410270

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.725

AC:

24259

AN:

33472

American (AMR)

AF:

0.316

AC:

14150

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.632

AC:

16515

AN:

26130

East Asian (EAS)

AF:

0.0642

AC:

2548

AN:

39692

South Asian (SAS)

AF:

0.460

AC:

39703

AN:

86232

European-Finnish (FIN)

AF:

0.488

AC:

26070

AN:

53416

Middle Eastern (MID)

AF:

0.670

AC:

3862

AN:

5766

European-Non Finnish (NFE)

AF:

0.598

AC:

664671

AN:

1111840

Other (OTH)

AF:

0.571

AC:

34502

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

17998

35996

53994

71992

89990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17798

35596

53394

71192

88990

<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:

0.584

AC:

88716

AN:

152006

Hom.:

27271

Cov.:

AF XY:

0.569

AC XY:

42280

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.712

AC:

29531

AN:

41470

American (AMR)

AF:

0.446

AC:

6816

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.629

AC:

2183

AN:

3470

East Asian (EAS)

AF:

0.0923

AC:

478

AN:

5180

South Asian (SAS)

AF:

0.439

AC:

2115

AN:

4816

European-Finnish (FIN)

AF:

0.466

AC:

4899

AN:

10524

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.597

AC:

40551

AN:

67956

Other (OTH)

AF:

0.607

AC:

1280

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1745

3490

5236

6981

8726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

720

1440

2160

2880

3600

<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:

0.591

Hom.:

76055

Bravo

AF:

0.585

Asia WGS

AF:

0.315

AC:

1097

AN:

3478

EpiCase

AF:

0.601

EpiControl

AF:

0.602

ClinVar

Significance: Benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2Other:1

Oct 30, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic 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:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 65% of patients studied by a panel of primary immunodeficiencies. Number of patients: 62. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.9

(source)

DANN

Benign

0.70

PhyloP100

-0.51

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