chr2-9555759-G-T

Position:

• chr2-9555759-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_003183.6(ADAM17):​c.-154C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 587,790 control chromosomes in the GnomAD database, including 9,370 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2069 hom., cov: 32)
  • Exomes 𝑓: 0.17 (7301 hom.)
• Consequence: ADAM17 NM_003183.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0100

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-9555759-G-T is Benign according to our data. Variant chr2-9555759-G-T is described in ClinVar as [Benign]. Clinvar id is 1279750.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.-154C>A		5_prime_UTR_variant	1/19	ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-834C>A		5_prime_UTR_variant	1/19		NP_001369706.1
ADAM17	NM_001382778.1	c.-1076C>A		5_prime_UTR_variant	1/19		NP_001369707.1
ADAM17	XM_047445610.1	c.-312C>A		5_prime_UTR_variant	1/20		XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.-154C>A		5_prime_UTR_variant	1/19	1	NM_003183.6	ENSP00000309968.3
ADAM17	ENST00000618923.2	n.-154C>A		non_coding_transcript_exon_variant	1/8	1		ENSP00000480552.1
ADAM17	ENST00000618923.2	n.-154C>A		5_prime_UTR_variant	1/8	1		ENSP00000480552.1

Frequencies

GnomAD3 genomes AF: 0.156 AC: 23676 AN: 152098 Hom.: 2070 Cov.: 32

Gnomad AFR AF: 0.0972

Gnomad AMI AF: 0.392

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0255

Gnomad SAS AF: 0.0949

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.172

GnomAD4 exome AF: 0.172 AC: 74839 AN: 435574 Hom.: 7301 Cov.: 6 AF XY: 0.170 AC XY: 37847 AN XY: 222672

Gnomad4 AFR exome AF: 0.0927

Gnomad4 AMR exome AF: 0.126

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.0195

Gnomad4 SAS exome AF: 0.0953

Gnomad4 FIN exome AF: 0.159

Gnomad4 NFE exome AF: 0.193

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.156 AC: 23670 AN: 152216 Hom.: 2069 Cov.: 32 AF XY: 0.152 AC XY: 11292 AN XY: 74414

Gnomad4 AFR AF: 0.0970

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.0253

Gnomad4 SAS AF: 0.0948

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.170

Alfa AF: 0.167 Hom.: 350

Bravo AF: 0.156

Asia WGS AF: 0.0810 AC: 285 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -

Mycobacterium tuberculosis, susceptibility to Benign:1

Likely benign, no assertion criteria provided

research

Laboratory Of Immunobiology And Genetics, Instituto Nacional De Enfermedades Respiratorias Ismael Cosio Villegas

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	13
DANN	Benign	0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs55790676; hg19: chr2-9695888;