rs12692386

Variant names:

• chr2-9555777-A-G
• rs12692386
• NM_003183.6:c.-172T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-9555777-A-G
• chr2-9555777-A-T

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.-172T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.656 in 500,398 control chromosomes in the GnomAD database, including 114,008 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (40565 hom., cov: 33)
  • Exomes 𝑓: 0.63 (73443 hom.)
• Consequence: ADAM17 NM_003183.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 1.89
• Publications: 38 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]

ADAM17 Gene-Disease associations (from GenCC):

• inflammatory skin and bowel disease, neonatal, 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ENSG00000271855 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-9555777-A-G is Benign according to our data. Variant chr2-9555777-A-G is described in ClinVar as Benign. ClinVar VariationId is 1227372.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.927 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.-172T>C		5_prime_UTR	Exon 1 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.-852T>C		5_prime_UTR	Exon 1 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.-1094T>C		5_prime_UTR	Exon 1 of 19	NP_001369707.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM17	ENST00000310823.8	TSL:1 MANE Select	c.-172T>C		5_prime_UTR	Exon 1 of 19	ENSP00000309968.3	P78536-1
	ADAM17	ENST00000618923.2	TSL:1	n.-172T>C		non_coding_transcript_exon	Exon 1 of 8	ENSP00000480552.1	A6H8L4
	ADAM17	ENST00000618923.2	TSL:1	n.-172T>C		5_prime_UTR	Exon 1 of 8	ENSP00000480552.1	A6H8L4

Frequencies

GnomAD3 genomes AF: 0.709 AC: 107826 AN: 152034 Hom.: 40515 Cov.: 33

Gnomad AFR AF: 0.934

Gnomad AMI AF: 0.851

Gnomad AMR AF: 0.537

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.229

Gnomad SAS AF: 0.553

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.809

Gnomad NFE AF: 0.680

Gnomad OTH AF: 0.715

GnomAD4 exome AF: 0.633 AC: 220428 AN: 348248 Hom.: 73443 Cov.: 5 AF XY: 0.634 AC XY: 114016 AN XY: 179884

African (AFR) AF: 0.934 AC: 8406 AN: 8998

American (AMR) AF: 0.459 AC: 4703 AN: 10244

Ashkenazi Jewish (ASJ) AF: 0.778 AC: 8092 AN: 10402

East Asian (EAS) AF: 0.205 AC: 4961 AN: 24224

South Asian (SAS) AF: 0.557 AC: 10745 AN: 19288

European-Finnish (FIN) AF: 0.550 AC: 13887 AN: 25236

Middle Eastern (MID) AF: 0.759 AC: 1136 AN: 1496

European-Non Finnish (NFE) AF: 0.680 AC: 155226 AN: 228398

Other (OTH) AF: 0.665 AC: 13272 AN: 19962

GnomAD4 genome AF: 0.709 AC: 107924 AN: 152150 Hom.: 40565 Cov.: 33 AF XY: 0.694 AC XY: 51653 AN XY: 74398

African (AFR) AF: 0.934 AC: 38845 AN: 41572

American (AMR) AF: 0.537 AC: 8199 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.779 AC: 2703 AN: 3472

East Asian (EAS) AF: 0.228 AC: 1175 AN: 5150

South Asian (SAS) AF: 0.552 AC: 2658 AN: 4812

European-Finnish (FIN) AF: 0.530 AC: 5609 AN: 10590

Middle Eastern (MID) AF: 0.812 AC: 237 AN: 292

European-Non Finnish (NFE) AF: 0.680 AC: 46222 AN: 67970

Other (OTH) AF: 0.713 AC: 1502 AN: 2106

Alfa AF: 0.674 Hom.: 20795

Bravo AF: 0.715

Asia WGS AF: 0.454 AC: 1579 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	-	Mycobacterium tuberculosis, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.70
PhyloP100		1.9
PromoterAI		0.48	Neutral
Mutation Taster		=291/9	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: rs12692386; hg19: chr2-9695906; COSMIC: COSV60400621; COSMIC: COSV60400621;