rs12474969

Variant names:

• chr2-9556938-G-A
• rs12474969
• ENST00000607241.2:n.1065G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000607241.2(ENSG00000271855):​n.1065G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 150,764 control chromosomes in the GnomAD database, including 4,646 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.23 (4646 hom., cov: 33)
• Consequence: ENSG00000271855 ENST00000607241.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.508
• Publications: 5 publications found

Genes affected

ENSG00000271855 (HGNC:):

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• neonatal inflammatory skin and bowel disease

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

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000607241.2. 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
There are no transcript annotations for this variant.

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000271855	ENST00000607241.2	TSL:6	n.1065G>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000271855	ENST00000716659.1		n.307+346G>A		intron	N/A
	ENSG00000271855	ENST00000716660.1		n.278+346G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34503 AN: 150652 Hom.: 4650 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.288

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.310

Gnomad EAS AF: 0.00520

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.266

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.229 AC: 34501 AN: 150764 Hom.: 4646 Cov.: 33 AF XY: 0.226 AC XY: 16606 AN XY: 73616

African (AFR) AF: 0.109 AC: 4532 AN: 41428

American (AMR) AF: 0.198 AC: 2974 AN: 14984

Ashkenazi Jewish (ASJ) AF: 0.310 AC: 1075 AN: 3470

East Asian (EAS) AF: 0.00521 AC: 27 AN: 5180

South Asian (SAS) AF: 0.249 AC: 1195 AN: 4800

European-Finnish (FIN) AF: 0.298 AC: 3041 AN: 10208

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.308 AC: 20743 AN: 67394

Other (OTH) AF: 0.266 AC: 557 AN: 2094

Alfa AF: 0.271 Hom.: 1163

Bravo AF: 0.210

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.6
DANN	Benign	0.84
PhyloP100		0.51

Splicing

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

Other links and lift over

dbSNP: rs12474969; hg19: chr2-9697067;