2-9497202-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003183.6(ADAM17):c.1695T>C(p.Thr565Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,614,228 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T565T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.012 ( 19 hom., cov: 32)

Exomes 𝑓: 0.014 ( 199 hom. )

Consequence

ADAM17
NM_003183.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -8.20

Publications

5 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=-0.88).

BP6

Variant 2-9497202-A-G is Benign according to our data. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in CliVar as Benign. Clinvar id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-8.2 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1818/152354) while in subpopulation NFE AF = 0.0165 (1124/68030). AF 95% confidence interval is 0.0157. There are 19 homozygotes in GnomAd4. There are 926 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 19 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6 link	c.1695T>C	p.Thr565Thr	synonymous_variant	Exon 14 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.1695T>C	p.Thr565Thr	synonymous_variant	Exon 14 of 19	1	NM_003183.6	ENSP00000309968.3		P78536-1

Frequencies

GnomAD3 genomes

AF:

0.0120

AC:

1820

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00195

Gnomad AMI

AF:

0.0669

Gnomad AMR

AF:

0.0109

Gnomad ASJ

AF:

0.0271

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0145

Gnomad FIN

AF:

0.0180

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0136

AC:

3410

AN:

251436

AF XY:

0.0143

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00705

Gnomad ASJ exome

AF:

0.0232

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0200

Gnomad NFE exome

AF:

0.0167

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0144

AC:

21044

AN:

1461874

Hom.:

199

Cov.:

AF XY:

0.0146

AC XY:

10609

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33480

American (AMR)

AF:

0.00771

AC:

345

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0225

AC:

588

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39698

South Asian (SAS)

AF:

0.0160

AC:

1380

AN:

86256

European-Finnish (FIN)

AF:

0.0192

AC:

1023

AN:

53420

Middle Eastern (MID)

AF:

0.0154

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0151

AC:

16758

AN:

1112000

Other (OTH)

AF:

0.0131

AC:

791

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

1166

2333

3499

4666

5832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

584

1168

1752

2336

2920

<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:

0.0119

AC:

1818

AN:

152354

Hom.:

Cov.:

AF XY:

0.0124

AC XY:

926

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.00195

AC:

AN:

41582

American (AMR)

AF:

0.0108

AC:

166

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0271

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.0143

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0180

AC:

191

AN:

10626

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1124

AN:

68030

Other (OTH)

AF:

0.0137

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

186

279

372

465

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0150

Hom.:

Bravo

AF:

0.0114

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

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 02, 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

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.24

(source)

DANN

Benign

0.68

PhyloP100

-8.2

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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