rs55794209

Variant names:

• chr2-9505503-C-A
• rs55794209
• NM_003183.6:c.1345-138G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 111 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003183.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	NM_003183.6	MANE Select	c.1345-138G>T		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.685-138G>T		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.448-138G>T		intron	N/A	NP_001369707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.1345-138G>T		intron	N/A	ENSP00000309968.3
	ADAM17	ENST00000926352.1		c.1423-138G>T		intron	N/A	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.1375-138G>T		intron	N/A	ENSP00000615343.1

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

African (AFR) AF: 0.00714 AC: 121 AN: 16940

American (AMR) AF: 0.0132 AC: 367 AN: 27838

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 398 AN: 16988

East Asian (EAS) AF: 0.0000310 AC: 1 AN: 32296

South Asian (SAS) AF: 0.00699 AC: 382 AN: 54626

European-Finnish (FIN) AF: 0.0804 AC: 2614 AN: 32526

Middle Eastern (MID) AF: 0.00395 AC: 10 AN: 2530

European-Non Finnish (NFE) AF: 0.0458 AC: 20289 AN: 443266

Other (OTH) AF: 0.0362 AC: 1202 AN: 33234

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

African (AFR) AF: 0.00737 AC: 306 AN: 41534

American (AMR) AF: 0.0186 AC: 285 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.0822 AC: 869 AN: 10566

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0466 AC: 3167 AN: 67982

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

Alfa AF: 0.0426 Hom.: 42

Bravo AF: 0.0250

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.67
DANN	Benign	0.72
PhyloP100		-0.49
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: rs55794209; hg19: chr2-9645632;