chr2-9497202-A-G

Variant names:

• chr2-9497202-A-G
• rs56237316
• NM_003183.6:c.1695T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003183.6(ADAM17):​c.1695T>C​(p.Thr565Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,614,228 control chromosomes in the GnomAD database, including 218 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T565T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (19 hom., cov: 32)
  • Exomes 𝑓: 0.014 (199 hom.)
• Consequence: ADAM17 NM_003183.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -8.20
• Publications: 5 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]

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 2-9497202-A-G is Benign according to our data. Variant chr2-9497202-A-G is described in ClinVar as Benign. ClinVar VariationId is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-8.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0119 (1818/152354) while in subpopulation NFE AF = 0.0165 (1124/68030). AF 95% confidence interval is 0.0157. There are 19 homozygotes in GnomAd4. There are 926 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 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.1695T>C	p.Thr565Thr	synonymous	Exon 14 of 19	NP_003174.3
	ADAM17	NM_001382777.1		c.1035T>C	p.Thr345Thr	synonymous	Exon 14 of 19	NP_001369706.1
	ADAM17	NM_001382778.1		c.798T>C	p.Thr266Thr	synonymous	Exon 14 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.1695T>C	p.Thr565Thr	synonymous	Exon 14 of 19	ENSP00000309968.3
	ADAM17	ENST00000926352.1		c.1773T>C	p.Thr591Thr	synonymous	Exon 15 of 20	ENSP00000596411.1
	ADAM17	ENST00000945284.1		c.1725T>C	p.Thr575Thr	synonymous	Exon 14 of 19	ENSP00000615343.1

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1820 AN: 152236 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.0180

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0136 AC: 3410 AN: 251436 AF XY: 0.0143

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00705

Gnomad ASJ exome AF: 0.0232

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0200

Gnomad NFE exome AF: 0.0167

Gnomad OTH exome AF: 0.0147

GnomAD4 exome AF: 0.0144 AC: 21044 AN: 1461874 Hom.: 199 Cov.: 31 AF XY: 0.0146 AC XY: 10609 AN XY: 727238

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.00771 AC: 345 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 588 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0160 AC: 1380 AN: 86256

European-Finnish (FIN) AF: 0.0192 AC: 1023 AN: 53420

Middle Eastern (MID) AF: 0.0154 AC: 89 AN: 5768

European-Non Finnish (NFE) AF: 0.0151 AC: 16758 AN: 1112000

Other (OTH) AF: 0.0131 AC: 791 AN: 60394

GnomAD4 genome AF: 0.0119 AC: 1818 AN: 152354 Hom.: 19 Cov.: 32 AF XY: 0.0124 AC XY: 926 AN XY: 74494

African (AFR) AF: 0.00195 AC: 81 AN: 41582

American (AMR) AF: 0.0108 AC: 166 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.0143 AC: 69 AN: 4828

European-Finnish (FIN) AF: 0.0180 AC: 191 AN: 10626

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0165 AC: 1124 AN: 68030

Other (OTH) AF: 0.0137 AC: 29 AN: 2116

Alfa AF: 0.0150 Hom.: 54

Bravo AF: 0.0114

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0167

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.68
PhyloP100		-8.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs56237316; hg19: chr2-9637331;