rs56237316

Positions:

• chr2-9497202-A-G
• chr2-9497202-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003183.6(ADAM17):​c.1695T>C​(p.Thr565=) 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 (★★).

• 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

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:):

ACMG classification

Verdict is Benign. Variant got -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 id is 472724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-9497202-A-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM17	NM_003183.6	c.1695T>C	p.Thr565=	synonymous_variant	14/19	ENST00000310823.8	NP_003174.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM17	ENST00000310823.8	c.1695T>C	p.Thr565=	synonymous_variant	14/19	1	NM_003183.6	ENSP00000309968	P1

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

GnomAD3 exomes AF: 0.0136 AC: 3410 AN: 251436 Hom.: 40 AF XY: 0.0143 AC XY: 1937 AN XY: 135884

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 SAS exome AF: 0.0158

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

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.00771

Gnomad4 ASJ exome AF: 0.0225

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.0192

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0131

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

Gnomad4 AFR AF: 0.00195

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0271

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.0180

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.0137

Alfa AF: 0.0149 Hom.: 26

Bravo AF: 0.0114

Asia WGS AF: 0.00404 AC: 15 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0167

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Inflammatory skin and bowel disease, neonatal, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs56237316; hg19: chr2-9637331;