2-9505503-C-A

Position:

• chr2-9505503-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_003183.6(ADAM17):​c.1345-138G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0372 in 812,398 control chromosomes in the GnomAD database, including 743 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.032 (111 hom., cov: 32)
  • Exomes 𝑓: 0.038 (632 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.488

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 2-9505503-C-A is Benign according to our data. Variant chr2-9505503-C-A is described in ClinVar as [Benign]. Clinvar id is 1183199.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0319 (4852/152154) while in subpopulation NFE AF= 0.0466 (3167/67982). AF 95% confidence interval is 0.0452. There are 111 homozygotes in gnomad4. There are 2388 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 111 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.1345-138G>T		intron_variant		ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.1345-138G>T		intron_variant		1	NM_003183.6	ENSP00000309968	P1
	ENST00000472619.2	n.135C>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.0319 AC: 4851 AN: 152036 Hom.: 111 Cov.: 32

Gnomad AFR AF: 0.00739

Gnomad AMI AF: 0.0615

Gnomad AMR AF: 0.0187

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0822

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.0384 AC: 25384 AN: 660244 Hom.: 632 Cov.: 9 AF XY: 0.0377 AC XY: 12921 AN XY: 342818

Gnomad4 AFR exome AF: 0.00714

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.0000310

Gnomad4 SAS exome AF: 0.00699

Gnomad4 FIN exome AF: 0.0804

Gnomad4 NFE exome AF: 0.0458

Gnomad4 OTH exome AF: 0.0362

GnomAD4 genome AF: 0.0319 AC: 4852 AN: 152154 Hom.: 111 Cov.: 32 AF XY: 0.0321 AC XY: 2388 AN XY: 74414

Gnomad4 AFR AF: 0.00737

Gnomad4 AMR AF: 0.0186

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.0822

Gnomad4 NFE AF: 0.0466

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0426 Hom.: 42

Bravo AF: 0.0250

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.67
DANN	Benign	0.72

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

Other links and lift over

dbSNP: rs55794209; hg19: chr2-9645632;