dbSNP rs883399: ADAM17:c.1915-146C>T (chr2-9493971-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003183.6(ADAM17):c.1915-146C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.521 in 611,270 control chromosomes in the GnomAD database, including 89,139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.51 ( 20448 hom., cov: 33)

Exomes 𝑓: 0.53 ( 68691 hom. )

Consequence

ADAM17
NM_003183.6 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.389

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.92).

BP6

Variant 2-9493971-G-A is Benign according to our data. Variant chr2-9493971-G-A is described in ClinVar as [Benign]. Clinvar id is 1188943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6 link	c.1915-146C>T		intron_variant	Intron 15 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.1915-146C>T		intron_variant	Intron 15 of 18	1	NM_003183.6	ENSP00000309968.3		P78536-1

Frequencies

GnomAD3 genomes

AF:

0.506

AC:

76941

AN:

151910

Hom.:

20435

Cov.:

show subpopulations

Gnomad AFR

AF:

0.445

Gnomad AMI

AF:

0.730

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.628

Gnomad EAS

AF:

0.0932

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.661

Gnomad NFE

AF:

0.595

Gnomad OTH

AF:

0.559

GnomAD4 exome

AF:

0.526

AC:

241602

AN:

459242

Hom.:

68691

AF XY:

0.526

AC XY:

127486

AN XY:

242482

show subpopulations

Gnomad4 AFR exome

AF:

0.457

Gnomad4 AMR exome

AF:

0.353

Gnomad4 ASJ exome

AF:

0.632

Gnomad4 EAS exome

AF:

0.0619

Gnomad4 SAS exome

AF:

0.458

Gnomad4 FIN exome

AF:

0.487

Gnomad4 NFE exome

AF:

0.595

Gnomad4 OTH exome

AF:

0.543

GnomAD4 genome

AF:

0.506

AC:

76988

AN:

152028

Hom.:

20448

Cov.:

AF XY:

0.495

AC XY:

36811

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.445

Gnomad4 AMR

AF:

0.415

Gnomad4 ASJ

AF:

0.628

Gnomad4 EAS

AF:

0.0928

Gnomad4 SAS

AF:

0.435

Gnomad4 FIN

AF:

0.468

Gnomad4 NFE

AF:

0.595

Gnomad4 OTH

AF:

0.556

Alfa

AF:

0.556

Hom.:

2965

Bravo

AF:

0.498

Asia WGS

AF:

0.292

AC:

1016

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

-0.92

CADD

Benign

1.1

DANN

Benign

0.77

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over