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. Variant got -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

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]

ENSG00000271855 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.-172T>C		5_prime_UTR_variant	Exon 1 of 19	ENST00000310823.8	NP_003174.3
ADAM17	NM_001382777.1	c.-852T>C		5_prime_UTR_variant	Exon 1 of 19		NP_001369706.1
ADAM17	NM_001382778.1	c.-1094T>C		5_prime_UTR_variant	Exon 1 of 19		NP_001369707.1
ADAM17	XM_047445610.1	c.-330T>C		5_prime_UTR_variant	Exon 1 of 20		XP_047301566.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.-172T>C		5_prime_UTR_variant	Exon 1 of 19	1	NM_003183.6	ENSP00000309968.3
ADAM17	ENST00000618923.2	n.-172T>C		non_coding_transcript_exon_variant	Exon 1 of 8	1		ENSP00000480552.1
ADAM17	ENST00000618923.2	n.-172T>C		5_prime_UTR_variant	Exon 1 of 8	1		ENSP00000480552.1

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

Gnomad4 AFR exome AF: 0.934

Gnomad4 AMR exome AF: 0.459

Gnomad4 ASJ exome AF: 0.778

Gnomad4 EAS exome AF: 0.205

Gnomad4 SAS exome AF: 0.557

Gnomad4 FIN exome AF: 0.550

Gnomad4 NFE exome AF: 0.680

Gnomad4 OTH exome AF: 0.665

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

Gnomad4 AFR AF: 0.934

Gnomad4 AMR AF: 0.537

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.228

Gnomad4 SAS AF: 0.552

Gnomad4 FIN AF: 0.530

Gnomad4 NFE AF: 0.680

Gnomad4 OTH AF: 0.713

Alfa AF: 0.675 Hom.: 12098

Bravo AF: 0.715

Asia WGS AF: 0.454 AC: 1579 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mycobacterium tuberculosis, susceptibility to Uncertain:1

Dec 21, 2023

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

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.70

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: rs12692386; hg19: chr2-9695906; COSMIC: COSV60400621; COSMIC: COSV60400621;