2-9494727-A-G

Position:

chr2-9494727-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003183.6(ADAM17):c.1824T>C(p.Ser608=) 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:4O:1

Conservation

PhyloP100: -0.513

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 made for transcript

Verdict is Benign. Variant got -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 id is 1169868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9494727-A-G is described in Lovd as [Benign].

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/exons	MANE	UniProt
ADAM17	NM_003183.6 linkuse as main transcript	c.1824T>C	p.Ser608=	synonymous_variant	15/19	ENST00000310823.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM17	ENST00000310823.8 linkuse as main transcript	c.1824T>C	p.Ser608=	synonymous_variant	15/19	1	NM_003183.6	P1	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

GnomAD3 exomes

AF:

0.500

AC:

125705

AN:

251400

Hom.:

35092

AF XY:

0.508

AC XY:

68996

AN XY:

135872

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 SAS exome

AF:

0.458

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

Gnomad4 AFR exome

AF:

0.725

Gnomad4 AMR exome

AF:

0.316

Gnomad4 ASJ exome

AF:

0.632

Gnomad4 EAS exome

AF:

0.0642

Gnomad4 SAS exome

AF:

0.460

Gnomad4 FIN exome

AF:

0.488

Gnomad4 NFE exome

AF:

0.598

Gnomad4 OTH exome

AF:

0.571

GnomAD4 genome

AF:

0.584

AC:

88716

AN:

152006

Hom.:

27271

Cov.:

AF XY:

0.569

AC XY:

42280

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.712

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.629

Gnomad4 EAS

AF:

0.0923

Gnomad4 SAS

AF:

0.439

Gnomad4 FIN

AF:

0.466

Gnomad4 NFE

AF:

0.597

Gnomad4 OTH

AF:

0.607

Alfa

AF:

0.592

Hom.:

52769

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:4Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inflammatory skin and bowel disease, neonatal, 1

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided

Benign:1Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2020	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Nov 12, 2023

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

DANN

Benign

0.70

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