rs2276338

Variant names:

• chr2-9505660-C-T
• rs2276338
• NM_003183.6:c.1345-295G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003183.6(ADAM17):​c.1345-295G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 375,760 control chromosomes in the GnomAD database, including 54,547 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (21232 hom., cov: 30)
  • Exomes 𝑓: 0.53 (33315 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.376
• Publications: 22 publications found

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]

ENSG00000239300 (HGNC:):

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 2-9505660-C-T is Benign according to our data. Variant chr2-9505660-C-T is described in ClinVar as Benign. ClinVar VariationId is 1245694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.1345-295G>A		intron_variant	Intron 11 of 18	ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.1345-295G>A		intron_variant	Intron 11 of 18	1	NM_003183.6	ENSP00000309968.3

Frequencies

GnomAD3 genomes AF: 0.518 AC: 78480 AN: 151574 Hom.: 21215 Cov.: 30

Gnomad AFR AF: 0.484

Gnomad AMI AF: 0.730

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.628

Gnomad EAS AF: 0.0912

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.562

GnomAD4 exome AF: 0.527 AC: 118018 AN: 224068 Hom.: 33315 Cov.: 2 AF XY: 0.521 AC XY: 62373 AN XY: 119636

African (AFR) AF: 0.497 AC: 3462 AN: 6960

American (AMR) AF: 0.355 AC: 3969 AN: 11174

Ashkenazi Jewish (ASJ) AF: 0.627 AC: 3967 AN: 6322

East Asian (EAS) AF: 0.0734 AC: 867 AN: 11814

South Asian (SAS) AF: 0.449 AC: 15716 AN: 34980

European-Finnish (FIN) AF: 0.496 AC: 4872 AN: 9826

Middle Eastern (MID) AF: 0.665 AC: 573 AN: 862

European-Non Finnish (NFE) AF: 0.599 AC: 77871 AN: 130068

Other (OTH) AF: 0.557 AC: 6721 AN: 12062

GnomAD4 genome AF: 0.518 AC: 78536 AN: 151692 Hom.: 21232 Cov.: 30 AF XY: 0.506 AC XY: 37482 AN XY: 74108

African (AFR) AF: 0.484 AC: 20016 AN: 41322

American (AMR) AF: 0.418 AC: 6373 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.628 AC: 2175 AN: 3464

East Asian (EAS) AF: 0.0908 AC: 468 AN: 5152

South Asian (SAS) AF: 0.434 AC: 2090 AN: 4820

European-Finnish (FIN) AF: 0.468 AC: 4899 AN: 10466

Middle Eastern (MID) AF: 0.670 AC: 197 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40479 AN: 67926

Other (OTH) AF: 0.559 AC: 1176 AN: 2104

Alfa AF: 0.570 Hom.: 15966

Bravo AF: 0.510

Asia WGS AF: 0.292 AC: 1015 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 10, 2018

GeneDx

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	-0.91
CADD	Benign	0.73
DANN	Benign	0.50
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2276338; hg19: chr2-9645789;