2-9502349-C-T

Variant names:

• chr2-9502349-C-T
• rs34367192
• NM_003183.6:c.1545-73G>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.1545-73G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,310,460 control chromosomes in the GnomAD database, including 151,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14253 hom., cov: 31)
  • Exomes 𝑓: 0.47 (136771 hom.)
• Consequence: ADAM17 NM_003183.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.44
• Publications: 12 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=-0.98).
• BP6: Variant 2-9502349-C-T is Benign according to our data. Variant chr2-9502349-C-T is described in ClinVar as Benign. ClinVar VariationId is 1188944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.51 is higher than 0.05.

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.1545-73G>A		intron	N/A	NP_003174.3
	ADAM17	NM_001382777.1		c.885-73G>A		intron	N/A	NP_001369706.1
	ADAM17	NM_001382778.1		c.648-73G>A		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.1545-73G>A		intron	N/A	ENSP00000309968.3
	ADAM17	ENST00000926352.1		c.1623-73G>A		intron	N/A	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.1575-73G>A		intron	N/A	ENSP00000615343.1

Frequencies

GnomAD3 genomes AF: 0.416 AC: 63080 AN: 151742 Hom.: 14257 Cov.: 31

Gnomad AFR AF: 0.306

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.353

Gnomad ASJ AF: 0.549

Gnomad EAS AF: 0.0303

Gnomad SAS AF: 0.343

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.614

Gnomad NFE AF: 0.514

Gnomad OTH AF: 0.468

GnomAD4 exome AF: 0.473 AC: 547772 AN: 1158600 Hom.: 136771 AF XY: 0.472 AC XY: 277357 AN XY: 587216

African (AFR) AF: 0.311 AC: 8509 AN: 27342

American (AMR) AF: 0.257 AC: 10797 AN: 41944

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 12714 AN: 23092

East Asian (EAS) AF: 0.0232 AC: 884 AN: 38078

South Asian (SAS) AF: 0.366 AC: 28425 AN: 77564

European-Finnish (FIN) AF: 0.456 AC: 18866 AN: 41382

Middle Eastern (MID) AF: 0.600 AC: 2724 AN: 4540

European-Non Finnish (NFE) AF: 0.516 AC: 441095 AN: 854150

Other (OTH) AF: 0.470 AC: 23758 AN: 50508

GnomAD4 genome AF: 0.416 AC: 63106 AN: 151860 Hom.: 14253 Cov.: 31 AF XY: 0.407 AC XY: 30232 AN XY: 74196

African (AFR) AF: 0.307 AC: 12688 AN: 41394

American (AMR) AF: 0.352 AC: 5369 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 1904 AN: 3470

East Asian (EAS) AF: 0.0302 AC: 156 AN: 5166

South Asian (SAS) AF: 0.342 AC: 1650 AN: 4818

European-Finnish (FIN) AF: 0.439 AC: 4616 AN: 10526

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.514 AC: 34935 AN: 67926

Other (OTH) AF: 0.465 AC: 983 AN: 2112

Alfa AF: 0.447 Hom.: 2840

Bravo AF: 0.403

Asia WGS AF: 0.204 AC: 708 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inflammatory skin and bowel disease, neonatal, 1 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.0090
DANN	Benign	0.85
PhyloP100		-3.4
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: rs34367192; hg19: chr2-9642478;